Title of Invention

FLUORESCENTLY TAGGED LIGANDS

Abstract

Library comprising a plurality of tagged non-peptiede iigands of formula (I): (Lig JL)M L(JT Tag) m (JTL(JLLig)m)p including and salts thereof comprising one or a plurality of same or different ligand moieties Lig each linked to a one or a plurality of same or different tag moieties Tag via same or different linker moieties L and same or different linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter; L is a single bond or is any linking moiety selected from a heteroatom such N, O, S, P, branched or straight chain saturated or unsaturated, optionally heteroatom containing, C1-600 hydrocarbyl and combinations thereof, which may be monomeric, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300.

Full Text

FLUORESCENTLY TAGGED LIGANDS The present invention relates to a library of tagged non-peptide ligands comprising one or a plurality of ligand moietie"s each linked to one or a plurality of different tag moieties; a process for the preparation thereof; a method for the rational design of a library and selection from the library of a tagged ligand; a kit comprising reactive non-peptide ligand(s) and reactive tagging substrate(s) for the preparation of the library of tagged non-peptide ligands; tagged non-peptide ligands associated with information on their pharmacology; novel tagged Ligands; novel ligand precursors and processes for the preparation thereof; the use of known and novel tagged ligands and libraries of tagged ligands in studying receptor binding such as G-protein coupled receptor (GPCR) binding or intracellular enzyme inhibition such as cyclic nucleotide phosphodiesterase inhibition and binding of drugs to drug transporters (eg nucleoside transporters or ATP binding gassette transporters); more specifically studying these interactions in cell populations or single cells such as acutely dispersed cells using techniques such as Confocal Microscopy and Fluorescence Activated Sorting and Fluorescence Correlation Microscopy. The adenosine-A1 receptor (A1-AR) is a GPCR which is found in a variety of tissues incfading brain heart, adipose tissue and muscle, and has been implicated in the pathophysiology of a number of conditions (Ralevic, V. and Bumstock, J (199S) Pharmacol. Rev. 50, 415). Currently the study of Ai-AR pharmacology can only be performed well in cells which can be grown in large numbers using for enample techniques such as radioligand binding. Autoradiography enables single cell studies but does not allow- direct reading of binding and can take up to 4 - 6 weeks to develop the film to obtain results of binding. To overcome this problem, a very few fluorescent ligands have been adapted for use in visualising receptors and obtaining quantitative receptor- ligand binding data in single cells, using confocal microscopy (CSLM), confocal plate readers, fluorescence polarisation plate readers, and fluorescence correlation spectroscopy (PCS). Confocal microscopy allows visualisation of a section through a cell, concentration of fluorophore at the cell edges indicates membrane receptor binding. FCS analyses the diffusion characteristics of fluorescent species, fast- diffusing free ligand can be distinguished from slowly-diffusing receptor-bound ligand and quantified simultaneously when the volume is localised to the cell membrane. McGrath et al TiPS November 1996 (Vol 17) 393 - 399 reviews the possibilities for using fluorescent ligands in place of more traditional radioactive ligands in the study of cell receptors to report the amount of ligand-receptor complex indicating the number of receptors, using confocal spectroscopy and fluorescence activated cell sorting (FACS). He states that many attempts have been made at conjugating fluorescent molecules to receptor ligands in the hope of identifying their binding sites, aimed mainly at localisation of the receptors rather than studying their properties. Some compounds are reported that fluoresce when bound to a receptor but which give low background noise in the aqueous phase. A reported objective was to produce a fluorescent drug which would remain fluorescent when bound to the receptor and would remain bound when unbound drug was washed away. Therefore there was a need for very high receptor binding affinity. Reviewed work includes fluorescent ligand binding to nicotinic receptors, beta adrenoceptors, opioid GPCR type receptors, histamine, neurotensin and alpha-adrenoceptors. The publication also reviews benefits of confocal microscopy. Efforts made to study the pharmacological properties of the ligands axe reported in only a few of the above cases. However very few efforts to visualise receptors or classes of receptors have been shown to work. Pharmacological properties are usually to some extent affected by linking of a fluorophore to any receptor binding ligand, and include change in binding affinity, and in activation or otherwise of receptor, ie agonist or antagonist properties. It is important that the pharmacology of the fluorescent ligand is known in any studies in order to quantify the binding results observed. In fact the synthesis of non-peptide fluorescent ligands for GPCRs presents serious problems. The few commercial non peptide fluorescent ligands for cell surface receptors that have been synthesised include histamine-BODEPY ™ FL and (pictured below) CGP12177-BODIPY ™ TMR (Molecular Probes): The BODfPY ™ (BDI) fluorophores were initially designed for attaching to proteins which present a much more uniform prospect for attaching: kits are available comprising a fluorophore and a set of reagents for universally attaching to most proteins. These give non specific attachments to any reactive site on the protein of interest and usually there is no need to know the nature or location of the attachment. However these proteins are larger molecules than the non-peptide ligands, including drugs such as XAC (xanthine 3mine congener) etc envisaged in the present invention. The ligand binding site for the many GPCR receptors is also usually deep within the transmembrane regions of the receptor and thus the challenge is to attach to the fluorophore in such a way as to retain pharmacological activity. None of these BDI fluorophores are concerned with the specific design of fluorescent agonists/antagonists with defined properties at GPCR's but rather with the fluorophore as an "add-on" probe. In summary therefore the availability of fluorescent ligands and in particular non- peptide fluorescent ligands suitable for FCS and CM binding studies is virtually non- existent. The preparation of such compounds is far from routine and few efforts have been made to establish pharmacology. McGrath above only looked at a few of the receptor types studied. There is moreover no unified approach in much of the prior art. Individual research has addressed fluorescent Ligand systems which are limited to specific drug classes and or to the use of specific fluorophores. Such systems are limiting in both the information which can be obtained and in the number of systems which can be investigated. Accordingly there is a need for novel selective fluorescent ligands for binding at desired receptors giving reliable and effective receptor visualisation and receptor selectivity with established pharmacology in terms of both affinity and agonist and antagonist properties. We have now applied a multidisciplinary approach to fluorescent ligand design to provide a library of rationally designed fluorescently tagged ligands and a process for preparation thereof that may be used in a method for selection of a fluorescently tagged ligand which is selective to a desired GPCR, having required defined pharmacological characteristics. The library is obtained from preferably non-peptide ligand precursors comprising chemical functionality for linking to any fluorophore to provide known or novel fluorescent ligands with linking at a desired site enabling selection of a fluorescent ligand providing retention of receptor binding capability and linking in manner not to interfere with receptor binding capability, or to modify binding capability in known manner. The linker precursors may also provide improved properties such as water solubility, on linking to a fluorescent moiety or any other desired non-hydrophilic probe. In the broadest aspect of the invention there is provided a library comprising a plurality of tagged non-peptide ligands of formula I including salts thereof comprising one or a plurality of same or different ligand moieties Lig each linked to a one or a plurality of same or different tag moieties Tag via same or different linker moieties L and same or different linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter, L is a single bond or is any linking moiety selected from a heteroatom such as N, O, S, P, branched or straight chain saturated or unsaturated, optionally heteroatom containing, C1-600 hydrocarbyl and combinations thereof, which may be monomelic, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300; Tag is any known or novel tagging substrate; m are each independently selected from a whole number integer from 1 to 3; p is 0 to 3 characterised in that linking is at same or different linking sites in compounds comprising different Lig, JL, L JT and/or - Tag and is at different linking sites in compounds comprising same Lig, JL, L JT and/or - Tag. Preferably the library does not comprise as Lig NECA, as Tag dansylamide or NBD, as each J a single bond and as L a methylene chain of C3-12. The innovation of the present invention relates to the design of specifically tagged ligands or "drugs" eg fluorescent ligands or "drugs" with known or selectable pharmacological properties. A key to this success is that each tag or fluorophore has a specific influence on the pharmacology of the resulting product, and it is incorrect to assume that the compound will retain the properties of the precursor drug. Preferably the library is constructed by the rational design of library members representing modifications in linking sites and ligand moieties, which can be used as a basis for selection of a tagged or fluorescent ligand retaining the properties of the precursor ligand. Preferably the library comprises a plurality of defined and well characterized tagged ligands, having verified properties corresponding to those of the non-tagged ligand. A GPCR ligand may be selected from any compound which is effective as an agonist or antagonist for an adenosine receptor, a beta-adrenoceptor, a muscarinic receptor, a histamine receptor, an opiate receptor, a cannabinoid receptor, a chemokine receptor, an alpha-adrenoceptor, a GAB A receptor, a prostanoid receptor, a 5-HT (serotonin) receptor, an excitatory aminoacid receptor (e.g. glutamate). a dopamine receptor, a protease-activating receptor, a neurokinin receptor, an angiotensin receptor, an oxytocin receptor, a leukotriene receptor, a nucleotide receptor (purines and pyrimidines), a calcium-sensing receptor, a thyroid-stimulating hormone receptor, a neurotensin receptor, a vasopressin receptor, an olfactory" receptor, a nucleobase receptor (e.g. adenosine), a lysophosphatidic acid receptor, a sphingolipid receptor, a tyramine receptor (trace amines), a free-fatty acid receptor and a cyclic nucleotide receptor or the like, preferably for a GPCR receptor for example a) an adenosine receptor antagonist b) an adenosine receptor agonist c) a beta-adrenoceptor agonist and d) a beta-adrenoceptor antagonist. Preferably a ligand is a non-peptide ligand. An inhibitor of intracellular enzymes is preferably e) an inhibitor of an intracellular enzyme such as an inhibitor of cyclic nucleotide phosphodiesterases; or a derivative or analogue mereof. A substrate of a drug transporter is any drug that is transported into or out of the cell via the transporter. An inhibitor of a drug transporter is any compound which binds to the transporter and prevents a substrate being transported. Thus, a tagged inhibitor can be used to bind to the transporter and localise it. A tagged substrate of the invention could be used to follow transport into or out of the cell and to test whether inhibitor drugs can prevent the transport of the tagged substrate. A substrate or inhibitor is preferably selected from a substrate or inhibitor of any equilibrium based drug transporters or ATP driven pumps such as a catecholamine transporter, a nucleoside transporter, an ATP-binding cassette transporter, a cyclic nucleotide transporter or the like. Preferably the library provides tagged ligands which are suited for surface cell receptor binding or for intracellular binding, or for penetrating or exiting live cells. Accordingly the library represents the rational design of compounds which are predicted to have retained pharmacology and properties suitable for specific binding applications. Each Tag may be independently selected from any entity which is known in the art of tagging molecules to form a marker or reporter group for detecting molecules and which may be used in analytical studies relating to the ligand, particularly for visualisation, and includes but is not limited to fluorophore tags as known in the art. An additional Tag may be present and may perform a function in situ, eg may be any laser activated Tag which is activated to have a local or targetted therapeutic or destructive effect. This allows in a first stage visualising the compound of formula I by means of a visualisation Tag, in a second stage activation of laser activated Tag, and optionally in a third stage visualising the compound of formula I or fragments thereof. For example a laser activated Tag may comprise malachite green which may be activated for targetted protein destruction. In a particular advantage, in the case that Tag is a chemical entity which might be anticipated to inhibit receptor ligand binding or to inhibit intracellular enzyme or drug transporter inhibition in or by a compound of formula I such inhibition is negated or dispelled by the presence of group L and/or of each J or by the chosen site of linking in one or more library members. Preferably one or more of each -Tag in one or more or each library compound is an entity -Fl and comprises any known or novel fluorophore, whereby the library comprises compounds of which one or more or all of which are of formula V (LigJL)m L (JT Fl)m (JT L (JLLig)m)p Preferably each compound of formula I or I' comprises one of a plurality of fluorophores and/or tags providing a library of differently fluorescently tagged ligands comprising one or a number of different fluorophores (preferably of different chemical composition, spectral characteristics etc); and/or providing a library of differently tagged ligands including at least one fluorescently tagged ligand; alternatively each compound of formula I or V comprises one of a plurality of precursor ligands Linked each to one or a plurality of different tags providing a library of same or differently tagged ligands of plural ligand type; alternatively each compound of formula I comprises one of a plurality of linkers linking a precursor ligand and at least one Tag at the same or different linking site; alternatively each compound of formula I comprises the same linker linking a precursor ligand and at least one Tag at different linking sites providing a Library of differently linked tagged ligands of different conformation or anticipated pharmacology and binding. In each case the library of the invention provides for the selection of a tagged ligand of desired binding affinity inhibition or transport at a desired receptor, intracellular enzyme or at or by a drug transporter with desired pharmacology, visualisation, mechanism or the like. wherein each JL and JT comprises J as hereinbefore defined and may be same or different and may derive from functionality originally present in Lig or L and Tag or L or a combination thereof, characterised in that linking is at same or different linking sites in compounds comprising different Lig, JL, L, JT and/or Tag, and is at different linking sites in the case of any two or more compounds comprising identical Lig, JL, L, JT and/or Tag. In one preferred embodiment the invention comprises a library of compounds of formula I as hereinbefore defined wherein Lig, JL, L, JT and Tag are the same in all compounds, and wherein the compounds differ by site of linking thereof. In a further preferred embodiment the invention comprises a library of compounds of formula I or F as hereinbefore defined wherein Lig and JL are the same in all compounds and L and JT are the same or similar in all compounds and Tag is different in some or all compounds. In a further preferred embodiment the invention comprises a library of compounds of formula I or F as hereinbefore defined wherein Lig- and -Tag are the same in all compounds and -L- is different in all compounds. The library may comprise from 3 to 250 tagged ligands. Preferably the library comprises from 1 to 10 families comprising 3 to 25 tagged ligands each family comprising a ligand moiety of a common ligand type and from 3 to 25 different tag moiety types at least one of which is a fluorescent tag, more preferably each of which is a different fluorescent tag; or the library comprises from 5 to 250 fluorescently tagged ligands of different ligand type and different fluorophore type. A library providing fluorescent ligands comprising different F1 is useful to enable studying binding, inhibition or transport with different colour fluorescence for example to distinguish from same colour native fluorescence or to distinguish plural types of binding site, enzyme, transporter or the like. It is known that ligands modified ie by linking to a fluorophore typically undergo a change in binding affinity, inhibition or transport and suitably the library of the invention comprises characterisation of the pharmacology of each compound including binding affinity or inhibition or transport for certain GPCRs, intracellular enzymes or drug transporters. Preferably the library includes information for each tagged ligand comprised in the library, relating to the pharmacology for binding to or inhibition of a GPCR receptor or to inhibition of an intracellular enzyme such as cyclic nucleotide phosphodiesterases, or inhibition of or transport by a drug transporter including designation as agonist, antagonist, substrate or inhibitor and measure of affinity or inhibition etc, enabling quantification of results. In the prior art methods of preparing ligands the linking sites have in many cases been non-specific or unknown, as in the case of Molecular Probes ligands, or at best have been specific or known but not predetermined, designed or rationalised for a desired effect. Preferably in the library of the invention tagged ligands comprise fluorophores linked at any of a number of linking sites at which ligand receptor binding, inhibition or transport is maintained to a greater extent or is modified or inhibited to a lesser extent. Preferably the library comprises tagged ligands designed from reaction of reactive precursor ligand(s) and reactive fluorophores having reactive site chemical functionality and suited for reaction with associated reagents, for site specific reaction and linking, wherein the design is the result of extensive investigation of all or many of the possible linking sites and the resulting pharmacological characteristics and selection of one or more linking combinations which provide favorable binding, inhibition or transport characteristics. Preferably Lig is selected from a) xanthine like structures including XAC, theophylline, caffeine, theobromine. dyphilline, enprofylline and the like; or fused biaryl structures including papaverine. dihydroquinilones such as cilostamide, dipyridamole, vinpocetine and the like: and analogues thereof; b) adenosine like structures including AD AC, NECA and analogues thereof: c) ethanolamine like structures including Salmeterol, salbutamol, terbutaline. quinprenaline, lobetalol. sotalol, bombuterol, fenoterol. roprotolol, tulobuterol. clenbuterol and analogues thereof; d) oxypropanolamine like structures including CGP12177, propranolol, practolol, acebutalol, betaxolol, ICI 11S551, alprenolol, celiprolol (celectol), metoprolol (betaloc), CGP20712A, atenolol, bisoprolol, misaprolol, carvedilol, bucindolol, esmolol, nadolol, nebivolol, oxprenoiol. xamoterol, pindolol, timolol and analogues thereof; e) xanthine like structures including XAC, theophylline, caffeine, theobromine, dyphilline, enprofylline, sildenafil, EHNA (erythro-9-(2-hydroxyl-3-nonyl)adenine), zaprinast and the like; or spiro bicyclic structures including bypyridines such as amrinone, imidazolines such as CI930, dihydropyridazinones such as indolan, rolipram, SB207499, and the like; or fused biaryl structures including papaverine, dihydroquinilones such as cilostamide, dipyridamole, vinpocetine and the like and analogues thereof. Linker L may perform a number of functions including preventing loss of affinity of a ligand when modified to comprise a fluorescent moiety, by distancing the fluorophore moiety from the ligand structure, in cases that modifying by direct linking of Lig and F1 would interfere with ligand binding, inhibition or transport in which case a linker L may be designed as a short, medium or long chain structure as appropriate. A library compound of formula I or I' may optionally comprise functionality J as hereinbefore defined derived from its synthesis by the reaction of one or more reactive group(s) of a linker precursor or its components, providing a linker moiety, with a reactive group of one or more ligand precursors providing a ligand moiety and reaction of one or more other reactive group(s) of the linker precursor with a reactive group of one or more tag precursors such as a fluorescent tag precursor providing a tag moiety. In a particular advantage of the present invention linker L and/or linking site or functionality J facilitates linking of fluorescent moiety and ligand, in cases that groups of respective moieties are not reactive, or that stereochemistry or other effects would inhibit linking, or that reaction of existing reactive groups in commercially available precursor ligands and fluorophores would require the inclusion of protecting groups for functionalities present therein, in which case a linker is usually derived from a short, medium or long chain structure. In a further advantage linker - L- may be derived from a tri-, terra-, penta- or hexa-functional precursor, linking 3 or more ligands Lig and tags F1, enabling modified or more complex binding, inhibition or transport and associated pharmacology, for example binding to a plurality of receptor sites to explore receptor dimerisation such as homo or heterodimerisation. In a further advantage of the invention linker L may confer properties facilitating crossing the cell membrane, hydrophobicity, hydrophilicity and the like as required, in which case a linker is usuolly any functionalised structure. Preferably L is selected from a saturated or unsaturated single or double bond, -O-, - S-, amine, COO-, amide, -NN- hydrazine; and saturated or unsaturated, substituted or unsubstituted C1-600, preferably C1-300, more preferably C1-100 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, wherein optional substituents are selected from any C1-20 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, carbonvl and the like.. More preferably L is selected from a single bond, -O-S-, amino; and branched or straight chain C1-50 alkyl. alkenyl, alkynyl, alkoxyjamino, cycloalky/, heterocyclic, aryl, heteroaryl, and combinations thereof sucri as aralkyl aralkylamino, aralkylamido and the like, optionally comprising one or more heteroatoms wherein heteroatoms are as hereinbefore defined, optionally substiruted as hereinbefore defined wherein substituents are selected from C1-12 aliphatic, aromatic or alicyclic substituents as defined, hydroxy, thiol, halo, amine, oxo, carbonyl, and the like. JL and JT may comprise functionality derived from a reactive group or site for linking to fluorophore and/or to iigand selected from a saturated or unsaturated single or double bond, -O-, -S-, 'amino, amido. hydrazine, carbonyl, oxo, alkyl, alkenyl, alkynyl, alkoxy, thioxy, and the like. In the case that L comprises a single or double bond, JL and JT if present may comprise functionality derived from a reactive group or site for linking linker and fluorophore derived from the fluorescent moiety and/or the ligand moiety. Preferably the moiety JLm L JTm comprises a mono, di, tri, terra, penta or hexa amino, alkylthio, alkoxy, carboxylic acid, and combinations thereof more preferably a mono, di or tri aminoalkylthio, amino alkoxy, alkoxy carboxylic acid, alkoxy amine and the like. Preferably JLm L JTm is selected from mono, di or tri amino menthane, amino ethane, thio ethane, ethane, amino acyl, from polypeptide, or from mono or polyether derivatives thereof eg diamine or dithio such as mono or polyethylene glycol di or tri amine or thio. Preferably a linker moiety JLm L JTm as hereinbefore defined comprises a single or double bond or a single atom or group as hereinbefore defined or comprises a mono-, di-, tri- or terrafunctional linear or branched or cyclic substituted or unsubstituted hydrocarbyl of formula -L.I- J[A]qLRL[A'qL.J' ]p A"qL" J" wherein each of J to J" is a linking site or functionality as hereinbefore defined independently selected from a single bond, methylene, alkyne, alkene, NR, O, NRCO, S, CO, NCO, CHHal, P and the like wherein R is H or C1-8 alkyl or cycloalkyl or forms part of a cyclic ring with N, Hal is any halogen selected from chlorine, iodine, bromine; and is present in any rational location in a group A to A"; each of A to A " is a group selected from -O-, -C(=O)-, C1-12 alkoxy, alkoyl, cycloalkyl, heterocyclic, alkyl, alkenyl, aryl, arylamide, arylamine, amino, thioalkyl, heteroaryl as hereinbefore defined and combinations thereof and the like, optionally substituted by groups selected independently from C1-3 alkyl, C1-5 alkoxy and the like; each of qL to qi," are independently-selected from 0 or 1 or indicates an oligomeric repeat and is from 2 to 30, or indicates a polymeric repeat unit and is from 31 up to 300. RL is a C, N or S atom or is a CRL', NRL', alkyl, cycloalkyl, heterocyclic, aryl heteroaryl, amine or thio moiety and provides for branching when p is 1 or 2; wherein RL' is H or C1-3 alkyl; and p is as hereinbefore defined and is 0, 1 or 2. Preferably each J, J' and J" independently is a single or double bond, NRL, -O or -S or -C(O) or -NRC(O) or -C(O)NR, as hereinbefore defined A is alkoxy preferably CH2CH2O (PEG) and oligomers thereof or is aralkylamine aralkylamide, aralkyloxy, or is alkyl, preferably (CH2)1- 12 RL is a C1-5 alkyl chain comprising or containing a single or double branching C atom when p is 1 or 2; p is 0, 1 or 2; A' and A" are each selected from C1-8 alkyl, amine, phenylamine, phenylamide; and qL is 0, 1, 2 to 30 or 31 to 300, and qL- and qL- are 0 or 1 More preferably JLm L JTm is a single bond or is of formula J AqL RLJ" wherein each of J and J" is amine or -O-, A is CH2CH2O, qL is 1-30 or 31 to 300 and RL is CH2CH2 or of formula JAqLRL(AT)J" wherein each of J, J' and J" independently is amine, -O or a single bond, qL is 1, 2 or 3 -30 or 31 to 300 and A is CH2CH2O or HNCH2CO or qL is 1 and A is C(O) or (CH2)1-8 or qL is 0, RL is CH or CH2CH, qL- is 0 or qL' is 1 and A' is CH2 and qL" is 0 preferably O(CH2CH2O)qLCH2CH2NH,O(CH2CH2O)qLCH2CH(CH2NH)NH, OCH(CH2NH)NH, -CH(CH2NH)NH, -C(O) NH-, -(CH2)1-8-, (-HNCH2CO-)1-3 (= - gly1-3-) - or the like. More preferably each compound of formula I or I' as hereinbefore defined comprises a moiety Lig and L as hereinbelow defined: Wherein: Lig.am is suitably of the formula, in either of the following forms given, including any of its possible linking configurations or sites: Lig.a 'm Wherein any or each of Ra1 to Ra4, X1 and X2 may comprise a linking site or functionality J as hereinbefore defined X1 and X2 are each independently selected from H, O, OR.a, NR.a, NHR.a; X1and X2 are each preferably O; each of R.a', R.a2, R.a3 and R.a4 independently is selected from H or C1-4 linear or branched alkyl, preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or isobutyl optionally mono or multi hydroxy or halo substituted, such as CH2OH, CH2F or CH2CHOHCH2OH; R.a4 is selected from a heteroatom O, S or substituted or unsubstituted amine or saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, and the like; preferably R.a4 is selected from optionally substituted aryl, cycloalkyl, alkyl, ketone, (di)amine, (di)amide, more preferably optionally substituted alkoxy, cycloalkyl, amine, amide, carboxylic acid or optionally o-, m- or p- substituted phenyl wherein substituents include aryl, alkyl, cycloalkyl, heteroaryl or heteroalkyl, amine, amide, carboxyl, carbonyl etc, for example substituents include, or R.a comprises, cyclohexyl, cyclopentyl, ethoxy, (CH2)2PhPh, CH2Ph, CONH(CH2)nCONH, CH2CONH(CH2)2NH, CH2PhNHCOCH2, CH2CH,OCOCH2, succinimidyl ester, NHCOCH2, CH2(CH3)NCOCH2, H2N(CH2)2NHCOCH2, H2N(CH2)sNHCOCH2, H2NNHCOCH2, CH2CONH(CH2)2NHCOCH2, HOPhCH2N(CH2CH3.HOAc)(CH2)2NHCOCH2, heterocyclic-(CH2)4CONH(CH2)2NHCOCH2, heterocyclic-NHCON(heterocyclic)COCH2 and the like; or Lig.a is of the formula Lig.a2- wherein any or each of Ra3 to Ra6, or a cyclic C or heteroatom may comprise a linking site or functionality J as hereinbefore defined each of CA1 and C.A2 is independently selected from C5-6 aryl, heteroaryl. cycloalkyl and heterocyclic, more preferably from phenyl, or aryl containing 1 or 2 ring heteroatoms, or heterocyclic containing 1 ring heteroatom and/or 1 ring -C=C- group; Each of up to seven R.a3 is a substituent of a ring carbon or a ring heteroatom and: is independently selected from H, halo, hydroxy, thiol, amine, COOH, hydrazine, cyano, saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, and wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, and the like, such as =O, OCH3, CH2Ph(OCH3)2, O(CH2)3CON(CH3)c.hex, N(CH2CH2OH)2, c.hex, COOCH2CH3, CH2CH3; or any two or more of R.a5 form a one, two or three ring fused cyclic structure, preferably comprising a fused 3 ring aryl, 5-heterocyclic, 6-heterocyclic structure having 4 ring atoms common with the fused bicyclic Lig.a"structure; and R.a is a moiety as defined for R.a3 above; and L.a is as hereinbefore defined for L or JL L JT and is suitably of formula L.I or subformulae as hereinbefore defined, more preferably is selected from a single bond, amino acid or amide such as a peptide or polypeptide for example gly or gly3, alkyl of formula -(CH2)n where n is 3 to S, preferably 3, 4 or 6, optionally including one or more heteroatoms or unsaturated groups, such as -0- or -S- or -CH=CH- and the like: Lig.b is suitably of the formula Lig.b including any of its possible linking configurations or sites: Lig.b wherein any or each of Rb1 to Rb5or Xb1 to Xb3 may comprise a linking site or functionality J as hereinbefore defined ring substituents X.b1 and X.b2 are independently selected from hydrocarbon such as alkyl or SRx, NRx.2 and ORx wherein (each) Rx is selected from H, C'1-5alkyl. alkenyl; ring heteroatom X.b3 is selected from -S-, -O- and -CH2-; Rb1 is selected from saturated or unsaturated, substituted or unsubstituted C1-4 aliphatic, or C1-3 alicyclic optionally including one or more heteroatoms N. O, S. P; wherein subsrituent(s) are selected from one or more cyclcalkyl, heterocyclic, hydroxy, oxo, halo, amine; preferably R.b1 comprises a carbonyl substituted by H, alkyl or a linear or cyclic primary, secondary or tertiary amine, substituted C1-3 alkyl, cycloalkyl or amide, more preferably cyclopropyl, or CONHC[. 3alkvl such as CONHEt or CH2OH and each of R.b2 and R.b is selected from H, halo, hydroxy, thiol, amine. COOH, CHO, hydrazine, cyano or saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, and the like, preferably from H, halo or hydroxy, preferably H or Cl; Rb4 is H; Rb5 is H or alkyl L.b may comprise a linking site or functionality J as hereinbefore defined; and is as hereinbefore defined for L or its subformulae, more preferably is saturated and unsaturated substituted or unsubstiruted C1-12 aliphatic or C1-24 aromatic as defined for L preferably including one or more heteroatoms O, S or N, cyclic or heterocyclic groups, more preferably is of formula L.I or its subformulae as hereinbefore defined, most preferably is ( CH2)m wherein m is 2 to 12, preferably 3, 4, 6 or 8, or is (Ph-CH2CONH)2 (CH2)2; Lig.c is suitably of the formula Lig.c including any of its possible linking configurations or sites: Where any or each of Re1 to Rc2 or OH, or a chain C or N may comprise a linking site or functionality J as hereinbefore defined * indicates an optically active centre and Wherein Re1 is C6-14 aryl optionally including one or more heteroatoms selected from H, O, optionally substituted by OH, Hal eg Cl, NH2, NHC1- 3alkyl, sulphonamide, oxoamine (-CONH2) and the like, more preferably mono, di or tri substituted phenyl or quinoline wherein substituents include OH, Cl or NH2, more preferably m-CH2OH, p- OH phenyl, m-,p-dihydroxy phenyl or m-,m-dihydroxyphenyl, m-,m- diCl, p-NH2 phenyl, p-OH, m-CONH2 phenyl or 5-OH, 8-quinoIine and the like, such as R.c is selected from saturated or unsaturated, substituted or unsubstiruted Ci-2o, preferably Ci_]2, branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any optionally substituted CM2 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, and the like and combinations thereof; Preferably R.c2 is selected from Ci-o branched or straight chain aliphatic, C6-io araliphatic optionally substituted by OH and optionally including heteroatoms selected from N,0, preferably including an ether O, such as selected from -(CH2)6OCH((CH2)3Ph), CHCH3(CH2)2Ph, CHCH3CH2Ph0H, C(CH3)2CH2Ph or from the structures: L.c may be present as R.c2 or may comprise a linking site or functionality J as hereinbefore defined, and is as hereinbefore defined for L and is suitably of formula L.I or its subformulae as hereinbefore defined, more preferably is selected from C1-12 alkyl, amide etc; Lig.d is suitably a non-peptide of the formula Lig.d including any of its possible linking configurations or sites: where any or each of Rd1 to Rd2 or OH, a chain C or N may comprise a linking site or functionality J as hereinbefore defined * indicates an optically active centre Wherein R.d1 is saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, and the like; Preferably R.d1 is substituted or unsubstituted C1-24 aralkyl or heteroaralkyl, including single ring and fused ring systems with (hetero)aryl or cycloalkyl rings, wherein optional substituents include C1-6 alkyl, alkoxy, ether, carbonyl, alkenyl, amine, amide each optionally carbonyl, amide, halo or OH substituted, or halo such as chloro or OH, preferably R.d' is unsubstituted or substituted alkyl, alkenyl, halo, amine, amide, carbonyl, ketone, ether substituted phenyl or naphthyl, illustrated as follows, most preferably mono-, di-, tri- or tetra substituted mono or polycyclic fused aryl or cycloaryl or heterocycloaryl such as phenyl, carbazole or structures shown below or spiro ring systems, most preferably mono-, di-, tri- or terra alkoxy alkyl, alkoxy alkoxy alkyl or CF3 substituted phenyl or unsubstituted or monosubstituted naphthalene or 5,6 ring systems most preferably of the structures: R.d2 is substituted or unsubstituted amine, saturated or unsaturated, substituted or unsubstituted C1-12 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano, and the like, more preferably amine, C1-6 branched or straight chain alkyl optionally including ether O, and optionally substituted by C6-10 aryl, for example i.pr, i.bu, or of the formula: L.d may be present as R.d2 or may comprise a linking site or functionality J as hereinbefore defined and is as hereinbefore defined for L and its subformulae and is suitably of formula L.I and its subformulae as hereinbefore defined, more preferably is a single bond or is as hereinbefore defined for L.a; Lig.e comprises a cell permeant moiety or is associated with a cell permeant L or F1 moiety and is suitably of the formula , in either of the following forms given including any of its possible linking configurations or sites: each X is independently selected from H, O, -OR.e2, N, HN, NR.e5 HR.e6, and aryl optionally substituted by ether; or X is aryl optionally alkyl or alkoxy substituted such as Ph-ortho-OCH2CH:CH3 ; where R.e is as defined above for R.e1 above or forms a fused cyclic ring together with the adjacent ring N atom; preferably 1 or 2 fused 5 ruembered cyclic rings; R.e5 is as defined above for R.e1 above or is selected from optionally substituted phenyl wherein optional substituents include ether such as o-ethoxy or o-propoxy, alkyl, OH and the like, sulphonyl, carbonyl and the like substituted by heterocyclic, or cyclic C5-8 alkyl such as methyl, piperazinyl, sulphonyl and the like; each of C.EI and C.E2 is independently selected from C5-6 aryl, heteroaryl. cyloalkyl and heterocyclic, more preferably from phenyl, or aryl containing 1 or 2 ring heteroatoms, or heterocyclic containing 1 ring heteroatom and/or 1 ring -C=C- group; Each of up to seven R.e11 is a substituent of a ring carbon or a ring heteroatom and: is independently selected from saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, and wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo. cyano, and the like, such as =O, OCH3, CH:Ph(OCH3)2, O(CH:)3CON(CH3)c.hex, N(CH:CH2OH);, c.hex, COOCH2CH3, CH2CH3; or any two or more of R.e11 form a one, two or three ring fused cyclic structure, preferably comprising a fused 3 ring aryl, 5-heterocyclic, 6-heterocyclic structure having 4 ring atoms common with the fused bicyclic Lig.eJ structure; and R.e12 is a moiety as defined for R.e11 above; Preferably Lig.e is of the formula Lig.e1 as hereinbefore defined in particular where R.e2 and R.e3 are respectively propyl and butyl; L.e may comprise a linking site or functionality J as hereinbefore defined and is suitably as hereinbefore defined for L.a. Linking sites J as hereinbefore defined are suitably of any nature and location, ie any sites, which do not inhibit binding, inhibition or transport. Receptor binding is complex, and may require a specific binding site to be available and/or require a specific fluorescent ligand conformation. The fluorescent ligands of the library of the invention may be characterised by different linking sites linking ligand and fluorescent moiety as hereinbefore defined. From a comprehensive knowledge of the binding, inhibition or transport behaviour and the specific target sites, which remain unchanged in the fluorescent ligands of the invention, v/e have been able to determine a method for selecting suitable linking sites for desired retention of binding, inhibition or transport and pharmacological properties. Freferably the compounds of formula I or F include compounds representing all operative linking configurations exposing possible binding, inhibition or transport site options. F1 may include any red, green, near in. blue or the like absorbing dyes and other classes of dyes. Suitably Fl is selected from dyes in particular including fluorescein. fluorescein derivatives including FITC, and fluorescein-like molecules such as Oregon Green™ and its derivatives, Texas red™, 7-nitrobenz-2-oxa-1.3-diazole (NBD) and derivatives thereof coumarin and derivatives, naphthalene including derivatives of dansyl chloride or its analogues or derivatives, Cascade Blue™. EvoBIue and fluorescent derivatives thereof, pyrenes and pyridyloxazole derivatives, the cyanine dyes, the dyomics (DY dyes and ATTO dyes) and fluorescent derivatives thereof, the Alexafluor dyes and derivatives, BDI dyes including the cornercially available Bodipy™ dyes, erythosin, eosin, pyrenes, anthracenes, acridines, fluorescent phycobiliproteins and their conjugates and fluoresceinated microbeads, Rhodamine and fluorescent derivatives thereof including Rhodamine Green™ including the tetramethylrhodamines, X-rhodarnines and Texas Red derivatives, and Rhodol Green™, coupled to amine groups using the isocyanate, succinimidyl ester or dichlorotriazinyl-reactive groups and other red, blue or green absorbing fluorescent dyes in particular red absorbing dyes as reviewed in Buschmann V et al, Bioconjugate Chemistry (2002), ASAP article. More preferably Fl is selected from fluorescein derivatives and fluorescein-like molecules such as Oregon GreenTM and its derivatives, Texas red™, 7-nirrobenz-2- oxa-l,3-diazole (NBD) and derivatives thereof, coumarin and derivatives, naphthalene including derivatives of dansyl chloride or its analogues or derivatives, Cascade Blue™, EvoBlue and fluorescent derivatives thereof, pyrenes and pyridyloxazole derivatives, the cyanine dyes, the dionics (DY dyes and ATTO dyes) . and fluorescent derivatives thereof, the Alexafluor dyes and derivatives, BDI dyes including the commercially available Bodipy™ dyes, erythosin, eosin, FITC, pyrenes, anthracenes, acridines, fluorescent phycobiliproteins and their conjugates and fJuoresceinated microbeads, Rhodamine derivatives thereof including Rhodamine Green™ including the tetramethylrhodamines, X-rhodamines and Texas Red derivatives, and Rhodol Green™. More preferably F1 comprises fluorescein, Texas Red ™, Cy5.5 or Cy5 or analogues thereof, BODIPY ™ 630/650 and analogues thereof, DY-630, DY-640, DY-650 or DY-655 or analogues thereof. ATTO 655 or ATTO 680 or analogues thereof, EvoBlue 30 or analogues thereof, Alexa 647 or analogues thereof. Suitably Fl is derived from any of the above commercially available fluorophores, comprising or modified to comprise a reactive group facilitating linking to a ligand by a moiety J as hereinbefore defined. Preferably Fl comprises any of the above commercially available fluorophores modified to form a derivative or group of derivatives suitable for visualising ligand binding, inhibition or transport in a library as hereinbefore defined comprising JT -t- F1 wherein JT is as hereinbefore defined and comprises functionality derived from linking to a precursor ligand as hereinbefore defined and may optionally comprise a linking group -t- which is a proximal unsaturated or aryl moiety, comprising a medial short, medium or long chain alkynyl or cycloalkyl moiety and comprising a moiety derived from linking via a reactive group as hereinbefore defined such as carboxyl, sulphonate or as a heteroatom such as O or S or methylene derived from linking at an alkylhalide such as methylbromide, haloacetanxide. sulphonate efter or the like electrophilic group. For example Fl may include a substituent -t- which performs a fluorescence modifying function, for example is a heteroaryl or alkenyl such as mono-, di- or tri - enyi group which shifts the fluorescence of the compound to the red part of the spectrum and raises the absorption max value, or performs a linking function. Preferred BODIPY™ (4,4-difluoro-4-bora-3a,4a-diaz-s-indacene) fluorophores include those which span the visible spectrum and include those listed in U.S. Pat. No. 4,774,339; U.S. Pat. No. 5JS7.2SS; U.S. Pat. No. 5,24S,7S2; U.S. Pat. No. 5,274,113; U.S. Pat. No. 5,433,896; U.S. Pat. No. 5,451,663. A preferred member of this group is selected from any heteroaryl substituted BODIPY ™ dyes as described in the above patents the contents of which are incorporated herein by reference. Suitably JT - t - F1 comprising a BODJPY ™ structure is characterised by a dipyrrometheneboron difiuoride core, optionally modified by one or two fused rings, optionally substituted by one or several substituents such as alkyl, alkoxy, aryl, heterocyclic and the like, wherein one substituent -t- is adapted for linking as hereinbefore defined to a ligand precursor as hereinbefore defined, the substituent -t- opdonally comprising a proximal unsaturated or aryl moiety, comprising a medial short, medium or long chain alkynyl or cycloalkyl moiety and comprising a moiety derived from linking via a reactive group as hereinbefore defined such as carboxyl, sulphonate or as a heteroatom such as O or S or methylene derived from linking at an alkylhalide such as methylbromide, haloacetamide, sulphonate ester or the like electrophilic group. F1 may include a substituent -t- as hereinbefore defined which is heteroaryl or alkenyl such as mono-, di- or tri -enyl group which shifts the fluorescence of the compound to the red part of the spectrum and raises the absorption max value as in US 5187288; or may include alkenyl substituent linked to one or more of an aryl, carbonyl or like group, preferably linked to a fatty acid sidechain comprising (CH- 2)nCO2H where n = 5 - 22 as in US 5330854, more preferably linked via an aryloxymethylene to a and carbonyl; or may include an aryl alkenyl aryl group as in US 6005113. More preferably -Fl is of the formula -F11: Wherein any or each of R1 to R7, or a ring atom may comprise a linking site or functionality J as hereinbefore defined R7 is N or C-R8; Substituents R1, R2, R3, R4, R5, R6and R8 which may be the same or different are H, halogen, nitro, sulfo, cyano, alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, arylalkyl, or acyl wherein the alkyl portions of each contain fewer than 20 carbons; or substituted or unsubstituted aryl or heteroaryl; preferably at least four of R1 to R8 are non-hydrogen, alternatively adjacent substituents Rl and R2 taken in combination and adjacent substituents R5 and R6 taken in combination form fused 6- membered (hetero) aromatic rings or including any of its possible linking configurations or sites: wherein any or each of R3, R4 or R7, or a ring atom may comprise a linking site or functionality J as hereinbefore defined each fused ring is optionally and independently substituted by H, halogen, nitro, sulfo, cyano, alkyl, perfluoroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, alkylthio, alkylamido, amino, (mono or dialkyl)amino (wherein the alkyl portions of each contain fewer than 20 carbons), or substituted or unsubstituted aryl, heteroaryl, arylamido, heteroarylaniido, aryloxy, heteroaryloxy, arylamino or heteroaryl ami no; or 1 to 2 additional fused benzo or heteroaroraatic rings that are optionally substituted or unsubstituted. Preferably any or all of R2'3 to R4,5 is heteroaryl, more preferably a single ring single heteroatom such as such as pyrrole, thiophene, furan or single ring di heteroatom structure such as oxazole, isoxazole, oxadiazole, imidazole, or multi ring such as benzoxazole, benzothiazole, benzimidazole, or multi ring one heteroatom structure such as benzofuran, indole, preferably thienyl. More preferably Fl is selected from the BODIPY core structures of formulae FL.A1 or FL.A2 as shown below, in each case = indicating the attachment site of a sidechain and including any of its possible linking configurations or sites: BODIPY TMR BODIPY FL ethylene diamine (X is CONH(CH:)2NH2) or BODIPY FL (X is COOH ) Or F1.A2 including any of its possible linking configurations or sites: linker precursors wherein linking may be at same or different reactive sites in different compounds as hereinbefore defined. Preferably the process is a combinatorial process. Preferably the process comprises the reaction of one or more ligand precursors of formula IV and/or IV IV (LigJL)m-L-YLn IV Lig YLign comprising one or more or different reactive groups YL or YLig forming a linking functionality J, JL or JT as hereinbefore defined with one or more of a plurality of analytical tagging substrates of formula V and/or V V YTm Tag V YTm L (JTTag)m comprising one or more or different reactive groups YT forming a linking functionality J or JT as hereinbefore defined and optionally one or more linking species VI or VF or VI" VI YLm L YLm wherein Lig, J, L, JT and Tag and each m is independently as hereinbefore defined wherein the or each compound of formula IV or IV is capable of reaction with the or each compound of formula V or V, optionally via the or each species VI or VF or VI" to form a plurality of compounds of formula I as hereinbefore defined. Preferably in some or each compound of formula V or V, Tag is F1 as hereinbefore defined, whereby the process is a process for preparing a library comprising a plurality of compounds of which one or more or all of which are of formula F as hereinbefore defined. Suitably reactive groups YLig, YL, YT have suitable reactive group functionalities for linking, as hereinbefore defined, for example by substitution or by addition or addition - elimination reaction. Substitution reaction is suitably selected from reaction of electrophilic and nucleophilic reactive sites as hereinbefore defined such as: Succinimide ester alcohols esters -OSu*, -H Succinimide ester alkoxides esters -OSu*, H or M+ Succinimide ester thiols thioesters -OSu*, -H Succinimide ester amine carboxamide -OSu*, -H Succinimide ester hydrazine hydrazide -OSu*, -H Addition reaction is suitably selected from cycloaddition or addition-elimination reaction of electrophilic and nucleophilic reactive sites in IV and V as hereinbefore defined: Electrophile Nucleophile Covalent Leaving Y Y Linkage, J Group azide alkyne triazole* none 2-acyl cyclic mono- dinucleophile 6.7-dihydro-lH-indazol-4(5H)-one H2O /di-ketone eg hydrazine 4,5,6,7-tetrahydro-lH-indazole H;0 (5 or 6 mem ring) l,4,5,6-tetrahydrocyclopenta[c]pyrazoIe H:0 5,6-dihydrocyclopenta[c]pvrazol-4(IH)-one H2O wherein * is [3+2] dipolar cycloaddition Preferably a compound of formula TV or IV' comprises no protecting group and is capable of reaction with a compound of V or V optionally via a compound of VI. without degradation of functionality by choice of reaction and of respective reactive sites; or a compound of formula IV or IV' comprises one or more protecting groups which are adapted for removal under ambient conditions, for example under neutral pH, room temperature or the like. Preferably the process comprises reaction wherein reactive groups Y are selected so as to enable reaction with a fully deprotected Iigand ie without the need for protecting groups or so as to enable reaction with protecting groups present which may be removed under mild conditions, for example one of YLig or YL or YT comprises amine or alcohol or thiol and the other comprises succinimide ester. In the case that choice of reactive groups requires protection of compounds of formula IV or IV, a protecting group is preferably such as to allow removal under mild conditions, preferably comprises benzyloxycarbonyl and the like which are removed at ambient conditions such as room temperature or under conditions which do not prejudice functional groups such as the glycosidic group in Lig.b. The process of the invention is characterised by a high yield of compounds of formula I or I' as hereinbefore defined by use of chemoselectivity and is superior to known methods which prejudice yields by use of non chemoselective reactive groups or protecting groups. Preferably the compounds of formula I or F are obtained by: reacting the unprotected primary alkyl amine group of a compound of formula IV as hereinbefore defined with a compound of formula V comprising a reactive succinimidyl ester group in solvent at ambient temperature without need for subsequent deprotection. In a particular advantage of the invention the method provides greater yield than with the prior art processes. Compounds of formula IV, IV', V, V or VI may be commercially available or may be prepared by known means. A linker may be installed as an independent entity or may be constructed as part of a synthetic process as hereinbefore defined, preferably is synthesised as an additional substituent on the ligand moiety or fluorescent moiety prior to reaction thereof. In a further aspect of the invention there is provided a process for the preparation of a compound of formula I as hereinbefore defined comprising the reaction of a compound of formula IV or IV' and a compound of formula V or V and optionally additionally VI, as hereinbefore defined. In a further aspect of the invention there is provided a process for the preparation of a compound of formula IV as hereinbefore defined comprising: obtaining where commercially available or preparing the ligand precursor Lig, by routes as known in the art, and reacting with linker precursor VI", if required, or components thereof, and/or generating one or more reactive sites Y or YLig or YL. Protection of IV may be required in which case reaction is followed by removing any protecting group present during the reaction, optionally replacing with a protecting group which may be removed under ambient conditions. A reactive group Y or YLIG or YL is preferably selected from groups as hereinbefore defined. Preferably the process comprises: a), e) ring closure of 5,6-diamino-l,3-dialkyl uracil with the appropriate substituted aldehyde under acid conditions with ferric chloride, b) reacting Lig.b- comprising a protected inosine derivative with chlorinating agent and linking the chloro derivative with the amine group of a suitably protected amine reactive linker H-L-PL wherein PL comprises N-benzyloxycarbonyl- to form Lig.b - L-PL and removing PL to generate Lig.b -L.b; preferably R.b1 comprises a OH terminating group and protected inosine comprises Acyl protecting groups or R.b1 comprises a stable group such as amine or amide and protected inosine comprises 2,2-dimethoxypropane protecting group; preferably the protected inosine is reacted with oxidising agent and protected alkylamine which is an N-alkylcarboxamide with removal of amine protecting group to generate a reactive ligand; c), d) reacting p-hydroxybenzaldehyde with formaldehyde under acid catalysis and protection of the resulting 4-hydroxy-3-hydroxymethylbenzaldehyde with dimethoxypropane to generate the resulting acetonide. Converting the Benzaldehyde to its corresponding epoxide and ring opening with a suitably protected linker such as Boc-L.c-H supplies Ligm-L-PL- Finally, deprotection under acid conditions supplies Lig.cLc or Lig.dLd for coupling to an appropriate tag. In a particular advantage of the present invention linker moiety L facilitates linking of fluorescent moiety and ligand moiety, in cases that moieties are not reactive, or that stereochemistry or other effects inhibit linking, or that reaction of existing reactive groups in commercially available compounds of formula IV or IV' and V or V would require the inclusion of protecting groups for functionalities present therein, in which case a linker is usually a difunctional short, medium or long chain structure. In a further advantage of the invention linker L may confer properties facilitating crossing the cell membrane, hydrophobicity, hydrophilicity and the like as required, in which case a linker is usually any functionalised structure. Preferably a linker precursor of formula VI as hereinbefore defined is selected from a heteroatomic species such as a species providing N, O, S, or P, or a branched or straight chain saturated or unsaturated, optionally heteroatom containing, C1-600 reactive hydrocarbon and combinations thereof, which may be monomelic, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300 and comprises reactive groups or sites for linking to ligand and fluorophore selected from hydroxy, alkoxy. thiol, fhioxy, amine, hydrazine. carbonyl and the like. In the case that a linker comprises a single bond, then a reactive site is usually present on the compound of formula IY'. whereby is reactive with compound of formula V or V". Preferably a compound of formula VI comprises three, four, five or six reactive sites, for linking 3 or more ligands and tags of formula IV or V. Preferably a linker precursor is selected from any substrate which generates or donates a moiety L as hereinbefore defined. Suitably a linker precursor of formula VI is a short, medium or long chain, comprising rationally designed functionality and comprising reactive sites providing functionality in moiety L as hereinbefore defined. Preferably a linker precursor of formula VI is a mono, di or mixed amine, hydroxy, thiol, carboxylic acid, acid chloride, acid fluoride, acid bromide, (acid halide), isocyanate NCO, isothiocyanate NCS, halide, alkylhalide, aldehyde, epoxide, sulphonyl chloride SO2Cl or hydrazine NHNH2, more preferably is selected from mono, di or tri amino menthane, amino ethane, ethanethiol, hydroxy ethane, amino acid, from polypeptide, or from mono or polyether derivatives thereof eg diamine or dithiol such as mono or polyethylene glycol di or tri amine or thiol. Preferably a linker precursor of formula VI is selected from any C1-12 substituted or unsubstituted alkylamine, aminoacid, cycloalkyl, aryl, heteroaryl, arallcyl, and the like providing one or more reactive end groups for linking to F1, more preferably selected from (di)amine, comprising cyclic or linear amine, more preferably diamine menthane, or diamino ethylene, amino acid or polypeptide, or from mono or polyether diamine such as polyethylene alycoldiamine, more preferably from H:2N(CH2)4NHCO2CH2Ph, H2N(CH2)5NHCO2CH2Ph, H2N((CH2)2O)2(CH2)2NHCO2CH2Ph and H2N(CH2)nNHBoc where n is 2 to S. Preferably a linker precursor comprises a linear or branched or cyclic substituted or unsubsriruted alkyl having one, two or three reactive sites, of formula YLm L.I YLm wherein L.I is as hereinbefore defined Preferably each YL is independently selected from H, CO2H, NH2, O. P. S and groups providing on reaction a single bond, alkyl such as methylene, alkyne, alkene, NH, NR, O, NRCO, S, CO, NCO, CHHal, P and the like wherein Hal is any halogen selected from chlorine, iodine, bromine, or wherein YL comprises protecting leaving groups ZL such as -NHCO2CH2Ph, H, OH, SH, halogen, amine, aliphatic, N-alkylcarboxamide, Boc and the like; In a further aspect of the invention there is provided a method for selecting a compound of formula I from a library as hereinbefore defined comprising the rational design of a library of compounds of formula I as hereinbefore defined using the process as hereinbefore defined, determining pharmacology for a plurality of or all compounds in the library and selecting a compound exhibiting desired pharmacology at a desired target. Preferably the method comprises preparing a preliminary library of compounds. conducting screens to assess binding, inhibition, transport and the like, selecting compound identified in the screen as having beneficial properties, and modifying or functionalising by nature of moieties or linking location of linking on the basis of the indications from the screen to prepare an optimised library. In a particular advantage j of the invention the molecular pharmacology and photochemistry from the screen ;. feedback into the design of the library. The linker strategy is in some cases specific for the tag to be used, whereby modifying the tag may require modifying the linker. We have surprisingly found that modifying a moiety without consequential modification of other moieties may result in an inactive compound which is for example incapable of binding. In a further aspect of the invention there is provided a known or novel compound of formula I or I as hereinbefore defined wherein the compound is associated with information relating to its pharmacological properties in the form of Spectral Properties given as Excitation Max and Emission Max. Fluorescence Lifetime and Emission quantum yield and Pharmacology defined in terms of cells expressing a GPCR receptor as hereinbefore defined or expressing an intracellular enzyme such as a cyclic nucleotide phosphodiesterase, or a drug transporter as hereinbefore defined and given as the Inhibition or Antagonism of receptor binding or of receptor functionality together with a value for the Inhibition (pKB) or Antagonism (pK1) binding constants, and optionally together with fluorescent images of the pharmacological binding in single living cells illustrating the defined inhibition or antagonism. Preferably the compound is associated with information relating to its pharmacological properties wherein pharmacology is defined in terms of a cell or protein wherein the cell expresses a GPCR, intracellular enzyme or drug transporter or the protein is a GPCR, intracellular enzyme or drug transporter preferably in terms of a CHO cell comprising GPCR receptors as hereinbefore defined, preferably selected from an adenosine receptor such as an Ar, A2A-, A2B- and A3-receptor, a beta-adrenoreceptor such as an β1, β2 and β3- adrenoceptors or like receptor, or comprises an inhibitor of an intracellular enzyme such as cyclic nucleotide phosphodiesterases or a substrate or inhibitor of a drug transporter as hereinbefore defined; more preferably in terms of CHO-cells expressing human adenosine A1- receptor or beta-adrenoceptor or an inhibitor of an intracellular enzyme such as an inhibitor of intracellular phosphodiesterases. The pharmacological properties are given as EC50 values for agonist stimulated - or pK1 values for antagonism of agonist stimulated second messenger generation, or substrate Km values or antagonist K, values for stimulation or inhibition of intracellular enzymes or drug transporters. Preferably a novel compound is of the formula I or I' as hereinbefore defined, more preferably is selected from formulae Lig.am L.a-Fl.an to Lig.em L.eFl.en as hereinbefore defined with the proviso that: a) whenLig is XAC ie in Lig.a when each of R.a and R.a" is propyl, R.a is Hand R.a4 is -Ph-OCH2CONH(CH2)2NH-, and L is a single bond or L is gly and n=3 or L is NCS, F1 is not fluorescein; or when Lig is XAC and L is a single bond or NCS, Fl is not fluorescein or NBD; b) when Lig is adenosine Fl is not Fmoc (CA 134:204756); or when Lig is ADAC , ie R.b' is CH2OH, R.b2 and R.b3 are H and L is -(Ph- CH2CONH)2(CH2)2- or L is a single bond, Fl is not fluorescein, NBD or Rhodamine; or when Lig is NECA (incorporating the moiety -(CH2)m) ie R.b2 and R.b3 are H and L is a single bond, or is -(CH2)m when m is 2,4,6,8 or 10 then Fl is not NBD, or when m is 3,4,6,8,10 or 12 then Fl is not dansyl; or when Lig is ;Y;-[2-(4-aminophenvl)ethyl]adeno3ine and L is (CH2)2PhNH, Fl is notFITC(CA 131:56155 (S)) d) when Lig is CGP12177 and L (R.d') is mono amine menthane, Fl is not BODEPY® TMR; or when Lig is CGP12177 and L is 1,1,4.4-tetramethyI butylamine, i.e C(CH3)2(CH2)2C(CH3)2NH- Fl is not BODEPY® FL, or when L is C(CH3)2(CH2)2C(CH3)2NHCSNH- then Fl is not FITC, eosin or erythosin; or when L is monoamine menthane, Fl is not FITC (CA 131:56155 (4)); or when Lig is CGP12177 and L is a single bond, Fl is not NBD; or when Lig is alprenolol i.e o-prop-2-enyl phenyl and L is -C(CH3)2- or a single bond, F1 is not NBD. Optionally additionally a) when Lig is XAC ie in Lig.a when each of R.a1 and R.a: is propyl, R.a3 is H and R.a4 is -Ph-OCH2CONH(CH2)2NH-, and L is a single bond Fl is not BODIPY ™ 630/650; or b) when Lig is ABEA, ie m is 4 and L is a single bond Fl is not BODIPY™ 630/650. Preferably a ligand or fluorescent ligand of the invention is an agonist which maintains its binding affinity and its functional activity or is an antagonist which maintains its binding affinity on linking or when linked to fluorescent moiety Fl. Fluorescent ligands may have affinity such that they bind permanently, semi- permanently or transiently, ie may retain bound or may be washed away when unbound ligand is washed away. Fluorescent ligands of the invention may be inherently optically active or may be functionalised, in known manner, to be optically active, and any such ligand may be present as a racemate or as one of its optically active isomers. In a further aspect of the invention there is provided a novel reactive ligand of formula IV or IV' as hereinbefore defined or library thereof useful for linking to any suitable tag of formula V or V as hereinbefore defined, with the proviso that when Lig is Lig.a and is 1,3-dialkyl xanuhine as hereinbefore defined wherein X1 and X2 are =0, R.a3 is H, R.a1 and R.a2 are both CH3 or both n-C3H7, then R.a4 is not 4-hydroxyphenol or PhOCH2CO2H; or when R-a1 and R.a2 are both n-C3H7, then R.a4 is not PhOCFLOCNHPhOH; PhOCH=OCONsuccin, FhOCH2CONH2, PhOCH2COMI(CH2):NH2; PhOCH2CONH(CH:)sNH2, PhOCH2COHMMH2. or PhOCH2CONH(CH2)2N(CH2CH3.HOAc)CH2PhOH;or when Lig is CGP12177 then L is not -C(CH3)2(CH2)2C(CH3,)2NH2 (CA 121:103436; or when Lig is aden, L is not H.CH:)2S(CH2)2NH2 (CA 125:21 S34S; or L is not (CH2)6NH2 or CH2CONH(CH2)6NH2 (CA 134:2043); or L is not (CH2)2NH2 or (CH2)20(CH2)20(CH2)2NH2 (CA 135:25706); or L is not (CH2)nNH2 where n is 2 - 12 (CA 103:715): or when Lig is alprenolol L is not (CH2)sNH2 or when Lig is propranolol L is not (CH2)4MH2 (CA 124:8848) or when Lig is alprenolol L is not CH2C(CH3)2NH2 (CA 108:215827) or when Lig is ICI 118551 L is not (CH2)2NH2 of when Lig is propranolol L is not (CH2)2NH2 (CA 9S:4564) Preferably a novel ligand-linker comprising a compound of formula IV wherein components are as hereinbefore defined and a reactive group YLig is as hereinbefore defined, preferably of formula Lig L.I or Lig.LI' as hereinbefore defined. In a further aspect of the invention there is provided a novel fluorophore linker of formula V or V as hereinbefore defined or library thereof. In a further aspect of the invention there is provided a kit comprising ligand precursors, linker precursors and tag precursors of formulae IV, IV', V, V and/or VI as hereinbefore defined for preparing a library of compounds of formula I as hereinbefore defined. In a further aspect of the invention there is provided the use of a fluorescent ligand of formula I or I' as hereinbefore defined or library thereof for visualising receptors or receptor binding, assessing pharmacological properties of the fluorescent ligand, in high throughput screening of novel chemical entities that bind to the target receptor, in inhibiting an intracellular enzyme or inhibiting a drug transporter or a substrate of a drug transporter, in studying drug transport or drugs suitable for transport, in distinguishing healthy or diseased tissue and the like. Preferably the use comprises using any fluorescence detection technique more preferably confocal microscopy or fluorescence correlation spectroscopy. Preferably the use allows to calculate ligand affinity constants and concentration of sub-populations of a receptor type, intracellular enzyme or drug transporter as hereinbefore defined. In a further aspect of the invention there is provided a method for receptor binding or inhibition, intracellular enzyme inhibition or drug transport or inhibition and visualisation comprising contacting a fluorescent ligand as hereinbefore defined with a sample in manner to facilitate binding or inhibition thereof or transport thereby, and detecting changes in fluorescence or location thereof. A sample may comprise cell material, selected from cells, cell extracts, cell homogenates, purified or reconstituted proteins, recombinant proteins or synthesised proteins and the like, and includes a target for the compound of formula I. Samples comprising cell material may be derived from plants, animals, fungi, protists, bacteria, archae or cell lines derived from such organisms. Animal or plant cells used to prepare the sample may be healthy or disfunctional and are optionally used in the diagnosis of a disease such as leukaemia or cancer. In a preferred embodiment of the invention the sample comprises mammalian cells, extracts and homogenates thereof. Preferably a sample comprises live cell material, more preferably including individual cells or sub cell compartments, most preferably comprising GPCRs, intracellular enzymes or drug transporters in living cells, membrane containing these proteins, solubilised receptors, enzymes or drug transporters or GPCR arrays. Cell material may be obtained in known manner by culturing cells or by expressing proteins in cells. In a preferred embodiment the cell material is a cell expressing a GPCR, enzyme or drug transporter. GPCR's are possibly the single most important class of targets for current and prospective drug therapies. More preferably the sample comprises GPCR receptors selected from adenosine A1 - , A2A-, A2B- and A3-receptors, β1. β2 and β3 adrenoceptors, or comprises inhibitors of intracellular enzymes such as cyclic nucleotide phosphodiesterases, most preferably CHO-cells expressing human adenosine A1 -receptor or beta-adrenoceptor or an inhibitor of an intracellular enzyme such as an inhibitor of intracellular phosphodiesterases. Cell material may be tagged prior to contact with the fluorescent ligand, for example by tagging with GFP, for example GFP tagged GPCR's, GFP tagged intracellular enzymes and GFP tagged drug transporters, or a native receptor, intracellular enzyme or a drug transporter to which a fluorescent antibody has been targetted, to allow visualising of the cell receptors, enzymes or transporters, and overlay with the fluorescent ligands. Receptors may be provided in membrane samples or in acutely dispersed cell samples, for example endogenous receptors such as A1-AR in acutely dispersed cells. The adenosine receptor binding site is located deep within the pocket of the receptor, whereby a fluorescent ligand with linker is a preferred fluorescent (ant)agonist. Whilst there is considerable freedom in modifying the ligand and retaining antagonist binding activity, it is harder to retain agonist activating activity, ie activating the receptors functions on binding. The method for drug transport of a substrate of a drug transporter would be to follow the uptake of the compound of formula I into the cell cytosol (if the transporter moves the drug into cells) OR after loading the cells with substrate to follow the dissappearance of the compound of formula I from the cells and its appearance in the extracellular medium (if the transporter moves the drug out of the cells - for example in the case that the transporter is an ATP-driven pump). Preferably the method comprises monitoring transport of a drug into a cell via an equilibrium transporter that moves the compound into the cell - then applying an inhibitor of this first equilibrium transporter, and monitoring the export of the drug from the cells via an ATP-driven pump transporter. The method of inhibition of a drug transporter may be monitored by detecting binding to the transporter on the cell surface. Preferably the method including detecting a change in fluorescence includes detecting a change in the intensity, excitation or emission wavelength distribution of fluorescence (single and multi photon), fluorescence lifetime, fluorescence polarisation or a combination thereof or the like. The optical response is detected by known means such as cameras, film, laser-scanning devices, fiuorometers, photodiodes, quantum counters, microplate, microscopes, fluorescent microscopes such as epifluorescence or confocal, cytometers, readers and the like, preferably CSLM, confocal plate readers, fluorescence polarisation plate readers or FCS. Where the sample is examined using a flow cytometer, examination of the sample optionally includes sorting components of the sample according to their fluorescence response. A method for binding or inhibition or detection according to the invention may be in vitro or in vivo. In a particular advantage of the invention the novel fluorescent ligands are suitable for use in combination with FCS enabling the study of ligand-receptor binding at the single molecule level. Because of the nature of the events being monitored FCS is ideal for the study of thermodynamic and kinetic features of molecular interactions in solution. Another particular advantage of the invention is that the FCS approach can be adapted to monitor ligand-receptor binding at the single molecule level using photon counting fluorescence intensity measurements. This removes any requirement for the molecules to be moving within the confocal volume. With ligands showing low background fluorescence it is not necessary to remove unbound ligand by washing before performing either confocal microscopy or FCS. It is therefore possible to measure fluorescence with time, in both time and concentration dependent manner. Confocal microscopy (CSLM) allows visualisation of a section through a cell showing concentration of fluorophore at the cell edges indicating membrane receptor binding. Visualisation is of a particular plane of focus such that a "slice" through an individual cell may be observed, as known in the art. Different coloured channels may be selected to visualise different fluorophore types. FCS is a non-invasive technique which analyses the diffusion characteristics of fluorescent species through a very small excitation volume ( analysing the partem of their photon emissions. Thus fast-diffusing free ligand can be distinguished from slowly-diffusing receptor-bound ligand and quantified simultaneously when the volume is localised to the cell membrane. Preferably the method incorporating FCS comprises measuring fluctuations in fluorescence intensity in a confocal volume of gives information about the speed of diffusion (i.e. mass) and concentration of the fluorescent molecules present. Thus free ligand (fast diffusing) and bound ligand (slow diffusing) can be quantified simultaneously on a single cell. FCS (fluorescence correlation spectroscopy) correlates fluctuations in fluorescence emission of particles to parometers such as particle mass and concentration for the study of molecular interactions in solution. FCS essentially monitors spontaneous fluorescence intensity fluctuations of fluorescently tagged molecules in a microscopic detection volume (10"l5l) through analysis by a tightly focused laser beam. These fluctuations provide information on the rate of diffusion or diffusion time of a particle which is directly dependent on the mass of the given molecule. When small and therefore rapidly diffusing molecules pass through the path of the laser they produce rapidly fluctuating fluorescence intensity patterns, whereas when larger molecules pass through the beam they produce bursts of fluorescence that are more sustained. Consequently the increase in the mass of a biomolecule, eg as a result of ligand binding, is detected as an increase in the diffusion time of the resultant biomolecule. Fluorescence microscopy may be used to localise receptors at single cell or sub cellular level with sensitivity and speed. In this way high affinity tagged ligands could help to elucidate molecular characteristics of GPCR receptor subtypes, such as adenosine and the like receptors, their regional distribution and cellular localisation. In a further aspect of the invention there is provided the use of a fluorescent target for the fluorescent ligand, for example, a Green Fluorescent Protein-tagged receptor, intracellular enzyme or drug transporter. In this case the spectral characteristics of the fluorescent ligand are chosen to allow separate detection of the location of both the fluorescent ligand and the fluorescent receptor, intracellular enzyme or drug transporter. Cross-correlation fluorescence correlation spectroscopy or fluorescence intensity measurements will then, allow the quantitative analysis of ligand-receptor, ligand-enzyme, ligand-drug transporter or drug transport interactions in a single measurement. This is distinct from prior art methods involving GFP-protein translocation assays and assays involving fluorescence energy transfer (FRET). Figure 1 exemplifies this approach. In a further aspect of the invention there is provided a cell surface GPCR modified on its N-terminus or a naturally occurring domain to express a short epitope tag for a commercially available antibody (e.g. myc, haemaglutinin, FLAG). This is then expressed in CHO cells and a fluorescent antibody to the tag sequence is used in living cells to provide two-colour analysis of fluorescent ligand-receptor interactions as described for GFP-tagged proteins above. In a further aspect of the invention there is provided CHO cells expressing a cell surface GPCR modified as claimed in Claim 37 for use with a fluorescent antibody to the tag sequence is used in living cells to provide two-colour analysis of fluorescent ligand-receptor interactions as described for GFP-tagged proteins above. In a further aspect of the invention there is provided a kit comprising a compound of formula I or I' as hereinbefore defined and a target therefore provided as a cell line, membrane derived from such a cell line or protein solubilised from that cell line. The cell derived material may be provided in one of three forms: (1) from cells expressing a green fluorescent protein tagged receptor, intracellular enzyme or drug transporter; (2) from cells expressing an epitope tag for a commercially available fluorescent antibody or (3) a wild-type protein for which, a specific fluorescent antibody is also provided. In an alternative embodiment there is provided a kit comprising a compound of formula I or I' as hereinbefore defined and a fluorescent antibody to a native protein which can be used in native (non-recombinant) cells. In each case, the spectral characteristics of the compound of formula I or F and fluorescent antibody or green fluorescent protein are selected to allow optimum two- colour cross-correlation fluorescence correlation spectroscopy (single or multiphoton). The invention is now illustrated in non-limiting manner with reference to the following figures and examples and accompanying synthesis schemes. In the Figures: Fig 1 shows binding of BODEPY-XAC to CHO-K1 cells expressing the human A1- receptor with a Green fluorescent protein tag attached to the C terminus, (a) binding of red ligand; (b) location of A1-GFP receptor and (c) co-localisation (yellow) of two signals obtained via confocal microscopy, more specifically Figure 1 shows images taken from confocal microscopy imaging of a) fluorescence derived from XAC BY- 630 binding to receptors on the surface of CHO cells observed at the red channel, b) fluorescence derived from green fluorescent protein fused to the C terminus of the human adenosine A1-receptor, expressed by CHO cells indicating receptor locations observed via the green channel and c) overlaid images from a) and b) showing overlap of fluorescence and therefore confirming ligand binding is specific to receptors. Fig 2 shows binding of BODIPY-ABEA to CHO-K1 cells expressing the human A1-receptor with a Green fluorescent protein tag attached to the C terminus. (a) binding of red ligand; (b) location of A1-GFP receptor and (c) co-localisation (yellow) of two signals obtained via confocal microscopy. In the Schemes: Scheme 1 shows synthesis routes for the synthesis of an adenosine receptor antagonist Lig - L - FIL Schemes 2 and 3 show synthesis routes for the synthesis of two adenosine receptor agonists Lig - L - FIL including the synthesis of ligand precursor Lig - L - ZL from linker precursor ZL'-L-ZL Scheme 4 shows synthesis routes for the synthesis of two beta adrenoceptor agonists Lig - L - FIL including the synthesis of ligand precursor Lig - L - ZL from linker precursor ZL'-L-ZL Examples A - C The following compounds are synthesised or modelled and binding affinity studied: Example A1 / B1 / C1 Adenosine receptors antagonists: XAC - BODIPY 630/650 (1) Example A2 / B2 Adenosine receptor agonists: Adenosine-BODIPY 630/650 (2) NECA-BODIPY 630/650 (3) (ABEA - BODIPY 630) APEA-BODIPY 630/650 (3a) AEIPEA - BODIFY 630/650 (3b) Example A3 / B3 Beta-adrenoreceotor agonists Salmeterol - BODIPY 630/650 (4) Clenbuterol - BODIPY 630/650 (9) Example A4 / B4 Beta-adrenoreceptor antagonists CGP12177-BODIPY 630/650 (5) Propranolol-BODIPY 630/650 (6) ICI118551-BODIPY 630/650 (7) Alprenblol - BODIPY 630/650(8) Example A5 / B5 Inhibitors of cvclic nucleotide phosphodiesterases XAC - BODIPY 630/650 (1) Materials and Methods The 1H NMR spectra were acquired on a Bruker AM 250 (250 MHz) spectrometer, in CDCl3 or DMSO-d6- Chemical shifts (5) are recorded in ppm with reference to the residual solvent signal/TMS. Coupling constants (J) are recorded in hertz, and signal multiplicities are described by s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), br (broad). Where given, assignments are made based on homonuclear correlation spectroscopy (COSY-45) and, where available, are in full agreement with literature values (Jacobsen KA et al.. J. Med. Chem. (1985), 2S, 1341-6). TOF ES+ found 974.399S (C50H55BF2N9O7S requires 974.4006) R, 12.5 min (35-100% v/v B, 30 min) 5H 0.S7, 0.90 (6H, overlapping t, J 9.3, N1-, N3-CU2CH2CH3), 1.14-1.25 (2H, m. C24H2), 1.36-1.62 (6H, m, C23H2, C25H2, N3-CH2CH2CH3), 1.68-1.7S (2H. m, N1/3- CH2C7/2CH3), 2.04 (2H, t. y 7.3, C~H:), 3.04-3.19 (6H, m, C18H2, C19H:, C26H2). 3.S6 (2H, t, J 7.4, ,V1/3-CH2:CH2CH3), 4.01 (2H, t, 7 7.1, NI/3-CH2CH2CH3), 4.52, 4.53 (4H, 2 x s. C15H:, C29H0, 6.95 (1H, d, 74.2), 7.05-7.10 (4H, m), 7.27-7.30 (3H, m), 7.35-7.40 (2H, m), 7.41 (1H, br s), 7.54-7.65 (3H, m), 7.70 (1H, s), 7.77 (1H, s), 7.S0-7.92 (2H, s), 8.01-8.23 (4H, m) (2 x CnH, 2 x C12H, 2 x C32H, 2 x C33H, C3SH, C36H, C3SH, C39H, C4IH, C43H, CME, C47H, C4SH, C49H, N9H, N17H, N20H, N27H) Example A2 - synthesis of adenosine based fluorescent agonists at the human Aj-adenosine receptor (Aj-AR) receptor based on 5'-/V- ethvlcarboxamidoadenosine fNECA) with maintained functional activity Compounds 2, 3, 3a and 3b were synthesised by reaction of suitably protected inosine derivatives, specifically with a chlorinating agent allowing introduction of a protected linker. Removal of protecting groups preceded conjugation of a fluorescent agent via the linking group. Scheme 2 Reagents and conditions: (a) Ac2O, pyridine, 40°C, 1 h, 97%. (b) POCl3, N,N- dimethylaniline, reflux, 5 min, S5%. (c) (i) H2N(CH2)4NHR, DffiA, EtOH, reflux, IS h, (ii) sat. NH3/MeOH, 0°C, 2 h. 66%. (d) H2, Pd/C, MeOH:H20:AcOH (7:2:1), r.t., 2 h, S0% (e) BODBPY 630/650-SE, DMF, r.t., 3 h, 63% 1. Adenosine-C4- BODIPY 630/650 (ABA-BY630) (2) ABA-BY630 was synthesised using the method and reagents and conditions described in Scheme 2 a-e in which R is COCH2Ph. ES+ found SS5.4 (C43H48BF2N9O7S requires 885.4) R, 22.5 min (5-100% v/v B, 30 min) 2. MECA-C4-PODPY 630/650 (AEEA-EY630) (3). N6-arninoburyl-5'-deoxy-5'-oxo-5'-ethylaminoadenosine (ABEA) was synthesised from commercially available reagents in 6 steps. The primary amine group of ABEA was acylated with the fluorophore BODrPY^630/650-X-succinimydyl ester (BY- 630, Molecular Frobes) to afford BY630-ABEA, which was purified by RP-HPLC (Scheme 3). The synthesis is shown in Scheme 3, with use of linker precursor of formula H2N(CH2)4 HNCOOCH2Ph: Scheme 3 Reagent: and Conditions: (a) 2.2-Dimethoxypropane. TsOH. acetone, r.t., 18 h. (b) TEMPO, BATE, MeCN:H2O (1:1). r.t., 4 h. (c) (i) SOCl2, DMF, CHC13, reflux, 6 h. (ii) EtNH2, CHCI3, 5°C. 30 min. (d) H2N(CH2)NHZ, DEEA, EtOH, reflux, 18 h. (e) 0.1 M HC1 (3q), 50°C, 4 h. (f) H2, Pd/C, MeOH:H2O:AcOH (9:0.9:0.1), r.t., 3 h. (g) BODIPY 630/650-X-SE, DMF, r.t., 4 h. Synthesis oflinlier modified lisand. compound of formula FY 2'.3'-Icoprop3'lideneiuo:ine 1: Inosine (5.36 2. 0.02 mol) and tosic acid monohvdrate (3.SO 2, 0.02 moll were suspended in a mixture of 2.2- dimethoxypropane (50 cm ) and acetone (200 cm ) and stirred for IS h. Sodium hydrogen carbonate (2.52 g, 0.02 mol) and water (40 cm3) were added and the suspension stirred for 15 min. The suspension was evaporated to constant volume and the crude product recrystallised from the residual water, yielding the acetonide 1 (3.71 g, 60%) as white needles; mp 266-268 °C (from H2O) (lit., 266 °C); [α]22D - 67.1 (c 0.59 in MeOH) (lit.. [a]20D -66.9 (c 0.S in MeOH)); δH(250 MHz; DMSO-d6) 1.31 (3 H, s, CH3), 1.53 (3 H. s. CH3), 3.53 (2 H, m, C5H2), 4.22 (1 H, m, C4'H). 4.93 (1 H, dd,J6.l and 2.5, C3'E0. 5.26 (1 H, dd,/6.1 and 2.9, CrH), 6.10 (1 H, d.J 2.9, C1'H), 8.10 (1 H, s, adenine CH), S.31 (1 H, s, adenine CH); δC(69.2 MHz; DMSO-40 25.2, 27.0 (2 x acetonide), 61.4 (C5), S1.3 (C4'), S3.8 (C3'), 86.6 (C2), S9.6(Cr), 113.1 (4°), 124.4(4°), 138.7 (CH), 146.1 (CH), 147.8 (4°), 156.5 (4°); m/z (ES+) 309 (MH+), 137 (M-ribose). 2',3'-IsopropyIidene-5'-oxoinosine 2: Acetonide 1 (3.08 g, 10 mmol), TEMPO (313 mg, 2 mmol) and iodosobenzene diacetate (7.09 g, 22 mmol) were dissolved in MeCN: H2O (1:1, 50 cm3) and stirred, with the exclusion of light, for 4 h. The solvents were carefully evaporated from the resultant suspension and the reaction residue sequentially triturated with acetone and diethyl ether to yield the acid 2 (2.67 g, 83%) as a white powder; mp 224-229 °C (from diethyl ether) (lit., 274-276 °C); (found: C, 4S.55; H, 4.3; N, 17.0. C13H14N4O6 requires C, 4S.45; H, 4.4; N, 17.4%); δH(250 MHz; DMSO-d6) 1.33 (3 H, s, CH3), 1.51 (3 H, s, CH3), 4.6S (1 H, d, J 1.6, C4'H), 5.36-5.44 (2 H, m, C2'H and C3H), 6.30 (1 H, s, C1'H), S.02 (1 H, s, adenine CH), 8.27 (1 H, s, adenine CH), 12.42 (1H, br s, NH; δC(69.2 MHz; DMSO-d6 25.1, 26.7 (2 x acetonide), 83.9, 85.S, 90.0 (4 x CH), 112.9 (4°), 124.4 (4°), 140.0 (CH), 145.8 (CH), 148.2 (4°), 156.8 (4°), 171.8 (CO); m/z (ES+) 323 (MH+), 137 (M- ribose). 6-Chloro-6-deoxy-5'-ethylamino-2',3'-isopropylidene-5'-oxo-5'-deoxyinosine 3: (N.B. Rigorously dry reaction conditions and under an inert atmosphere) acid 2 (967 mg, 3 mrnol), was suspended in CHCl3 (15 cm3) to which was added N,N-DMF (581 µL, 7.5 mrnol) and SOCl2 (1.09 cm3, 15 mrnol). The suspension was placed in a hot oil-bath and maintained at reflux for 6 h. The resultant solution was evaporated and the yellow oil dissolved in THF (20 cm3) at 5 °C. Ethylamine (2.0 M solution in THF, 3.75 cm3, 7.5 mrnol) was added drop wise, stirred at 5 °C for 15 min and allowed to warm to room temperature. The solvent was evaporated, the residue dissolved in DCM (25 cm") and washed with water (2 x 20 cm3) and saturated brine solution (2 x 20 cm3). The organic fraction was dried and evaporated to leave a yellow oil that was purified by column chromatography on silica (5 % MeOH-DCM) to give the title compound Z (525 mg, 48%) as a yellow syrup; [α]19D -12.9 (c 0.50 in CHCb); 8H(250 MHZ; CDC13; Me4Sn 0.7S (3 H t, J 1.3, CH2CH3), 1.41 (3 H. s. CH3\ 1.64 (3 H, s. CH3) 2.90-3.11 (2 H, m, CH2CH3) 4.74 (1 H, d, J 1.9, C4'H) 5.46 (1 H, dd, J 62 and 2.3, C2'H), 5.54 (1 H, dd, J 6.2 and 1.9, C3'H), 6.24 (1 H, d, J 2.3, C1'H), 6.28 (1 H, br s, NH), 8.35 (1 H, s, adenine CH), S.6S (1 H, s, adenine CH); 5C(69.2 MHz; CDCl3; Me4Si) 14.2 (CH2CH3), 25.0, 26.9 (2 x acetonide), 33.9 (CH2CH3), S2.9, S3.4, 36.7, 92.0 (4 :•; CH). 114.6 (4°), 132.3 (4°), 144,3 (CH), 150.9 (4°), 151.9 (4°), 152.2 (CH), 16S.1 (C=O); m/z (ES-) 366 ((M-H)-), 153 (M-ribcse). N6-(4-BenzyloxycarbonyIaminobut3'I)-5?-ethyIamino-2',3'-isopropyIidene-5'- oxo-5'-deoxyadenosine 4: Chloride 3 (337 mg, 0.92 mrnol) was dissolved in EtOH (10 cm3) to which was added yV-benzyIoxycarbonylbutan-l,4-diamine (305 mg, 1.37 mrnol) and DIEA (159 µL, 0.92 mrnol). The solution was placed in a hot oil-bath and maintained at reflux for 18 h. The resultant solution was evaporated and the yellow oil purified by column chromatography on silica (2.5 % MeOH-DCM) to give the title compound 4 (445 mg, SS%) as a pale yellow gum: δH(250 MHz; CDC13; Me4Si) 0.99 (3 H, t, J 7.1, CK2CH3), 1.43 (3 H, s, CH3), 1.55-1.71 (7 H, m, CH3 and 2 x CH2), 3.20-3.35 (2 H, m, CH2), 3.55-4.01 (4 H, m, CH2CH3 and CH2), 4.81 (1H, s, CH), 5.10 (3 H, m, benzyl CH2 and CH), 5.51 (1 H, d, J5.9, CH), 5.71 (1 H, d, J5.9, CH), 6.10 (1 H, br s, NH), 6.16 (1 H, br s, NH), 7.30-7.36 (5 H, m, aromatics), 7.86 (1 H, s, adenine CH), S.22 (1 H, s, adenine CH); 5C(69.2 MHz; CDC13; Me4Si) 13.7 (CH2CH3), 25.1, 26.6 (2 x acetonide), 26.8, 27.0, 40.0, 40.4 (4 x CH2), 61.5 (CH2CH3), 66.6 (benzyl CH2), 84.1, 84.7, 87.0, 91.6 (4 x CH), 113.7 (4°), 123.1 (C), 128.5 (CH), 136.7 (4°), 139.9 (CH), 152.S (CHI, 154.9 (4°), 156.5 (CH), 169.4 (C=0); m/z (ES+) 554 (MH+), 341 (M-ribose). N6-(4-Benzyloxycarboaylaminobutyl)-5'-ethylamino-5'-oxo-5'-deoxyadenosine 5: Adenosine derivative 4 (261 mg, 0.47 mmol) was dissolved in 1 M HCl(aq): 1,4- dioxane (1:1, 4 cm3), placed in a 50 °C oil-bath and stirred for 4 h. The resultant solution was adjusted to ~pH 8 (satd. NaHCO3(aq)), saturated with NaCl and extracted with EtOAc (3*5 cm3). The combined organic fractions were dried and evaporated and the crude product purified by preparative layer chromatography (10 % MeOH- DCM) to give the title compound 5 (160 mg, 66%) as a colourless oil; 5H(250 MHZ; DMSO-d6;) 1.08 (3 H, t, J 7.2, CH2CH3), 1.45-1.62 (4 H, m, C2H2 and C3E2), 2.98- 3.06 (2 H, m, C1H2), 3.17-3.26 (2 H, m, CH2CE3), 3.37-3.53 (2 H, m, C4H2), 4.12- 4.16 (1 H, m, C3H), 4.31 (1 H, d, J 1.1, C4H), 4.58-4.65 (1 H, m, C2H), 4.99 (2 H, s, benzyl CH2), 5.56 (1 H,d, J6.5, C2'-OH), 5.76 (1 H, d, J4.2, C3OH), 5.96 (1 H, d, J 1.6, CrH), 7.25-7.34 (6 H, m, aromatics and NH), 8.01 (1 H, br s, carbamate NH), 8.27 (1 H, s, adenine CH), 8.39 (1 H, s, adenine CH), 8.94 (1 H, t, J5.6, amide NH); 5C(69.2 MHz; DMSO-40 14.9 (CH2CH3), 26.6, 27.1, 33.4, 39.5, 40.3 (5 x CH2), 65.3 (benzyl CH2), 72.2, 73.3, S4.9, 88.0 (4 x CH), 120.2 (4°), 127.9 (CH), 128.5 (CH), 137.5 (CH), 140.6 (4°), 152.6 (CH), 154.9 (4°), 156.3 (4°), 169.3 (4°); m/z (ES+) 514 (MH+). A^-(4-Aminoburyl)-5'-ethylamino-5'-oxo-5'-deoxyadenosine (ABEA) 6. Adenosine derivative 5 (4S mg, 0.09 mmol) was dissolved in MeOH:H20:AcOH (9:0.9:0.1, 5 cm3), to which was added 10 % Pd/C (10 mg). The flask was evacuated, filled with hydrogen (balloon) and stirred vigorously for 3 h. The reaction mixture was filtered through celite and the celite washed with IvIeOH. The combined organic filtrates were evaporated and the resultant oil evaporated again from IvleCN (2 * 15 cm3) to give the title compound 6 (35 mg, quant.) as a colourless oil; ΔH(250 MHz; DMSO-d6) 1-08 (3 H, t, 77.2, CE2CH3), 1.46-l.SS (6 H, m, 2 x CH2 and NH2), 2.63 (2 H, t, 76.8, CH2), 3.16-3.29 (2 H, m, CH:CH3), 3.40-3.52 (2 H. m. CH2)r 4.10-4.15 (1 H, m, C3'H), 4.30 (1 H, d, J 1.3, C4H), 4.53-4.62 (1 H, m. CrH), 5.96 (1 H d. J 7.7, CrH ), 8.05 (1 H, br s, NH), 8.27 (1 H, s, adenine CH). S.3? (1 H, s. adenine CH), S.95 (1 H, t, J5.6, amide NH); m/z (ES+) 380 (MH+). Synthesis of fluorescent ligand, compound of formula I ABEA-BY630 (3): ABEA 6 (5.74 mg, 15.1 ammol) was dissolved in N.N-DMF (1 cm3) under an inert atmosphere and with the exclusion of light. A solution of Bodipy 630/650-X-succinimidyl ester (Molecular Probes) (5.0 mg, 7.55 µmmol, 1 cm3 N,N- DMF) was added and the reaction stirred for 4 h. The solution was evaporated and the crude product purified by preparative layer chromatography (10 % MeOH-DCM) to give the title compound 7 (3) (5.24 mg, 75%) as a purple powder; m/z (ES+) found 947.37 (C45H51BF2N10O7SNa requires 947.36). ABEA-BY630 3. NECA - C5 - BODIPY 630/650 (APEA-BY630) (3a) APEA-BY630 was obtained having the formula: This compound was synthesised using the method of Scheme 3 as described for Compound (3), with use of linker precursor of formula H:N(CH2)5NHCOOCH2Ph: N6-(8-Amino-3,6-dioxaoctyl)-5'-ethylamino-5'-oxo-5'-deoxyadenosine3: ΔH(400 MHz; DMSO-d6) 1.05 (3H, t/7.1, Et CH3), 1.86 (2H, br s, -NH2), 2.71-2.80 (2H, m, linker CH2), 3.17-3.26 (2H, m, Et CH2), 3.41 -73 (1 OH, m, 5 x linker CH2), 4.15 (1H, br m, C3'H), 4.34 (1H? s, C4'H), 4.47-4.54 (1H, m, C2*H), 5.95 (2H, br s, C2'-OH, C3'- OH), 6.01 (1H, d J 7.5, CrH), 7.92 (1H, br s, C6-NH), 8.31 (1H, br s, adenine CH). 8.44 (1H, s, adenine CH), S.95 (1H, U5.6, amide NH). ABIPEA-BY630 was obtained having the formula: TOF ES+ found 9S5.3993 (C47H56BF:N10O9S requires 9S5.4013) R, S.3 min (35-100% v/v B, 25 min) Example A3 -Synthesis of 3-Adrenoceptor agonists 1. Salmeterol-BODIPY 630/650 (4) and Derivative-Salmeterol-BODIPY 630/650 (4a) Salmeterol is linlced to fluorophore via two different linking sites, in the following syntheses In a first approach, a linker is substituted onto the salmeterol side-chain through which the fluorophore is subsequently attached. In the second approach the native alkyl side-chain of salmeterol is replaced with a linker and fluorophore. In this case, according to the invention, retention of binding, fluorescence and activity are uncertain and must therefore be verified and information provided with the fluorescent ligand, to provide a useful compound. All of the following molecules rely upon the synthesis of the same two linker moieties as shown in Scheme 4 and described above, (where the hydrocarbon chain length can be easily varied, or altered chemically to e.g. an ethylene glycol structure to improve solubility). Example A4 -Synthesis of (3-Adrcnoceptor antagonists All of the following molecules rely upon the synthesis of the same two linker moieties as shown in Scheme 4 and described in Example A3, (where the hydrocarbon chain length can be easily varied, or altered chemically to e.g. an ethylene glycol structure to improve solubility). The adenosine-A1 receptor (A1-AR) is a G-protein coupled receptor which is found in a variety of tissues including brain, heart, adipose tissue and muscle. By conjugating the ArAR antagonist xanthine amine cogener (XAC) to the fluorophore BODIPY®-630/650 (BY630), we have synthesised a fluorescent A1-AR ligand, XAC-BY630, to allow visualisation of this receptor in living cells. [3H]DPCPX binding alongside cyclic AMP and inositol phosphate accumulation assays were performed on CHO-A1 cells expressing the human A1-receptor. Images were acquired using a Zeiss LSM510 confocal microscope using CHO-A1 cells grown to 50% confluency on 8-well Labtek™ plates in Dulbecco's Modification of Eagle's Medium:Ham's F12 containing 5% foetal calf serum and 2mM glutamine. Cells were washed twice with HEPES-buffered saline prior to incubation at 22°C with compounds as indicated. Spectroscopic analysis of XAC-BY630 and BY630 itself showed that their peak excitation (630, 632nm, respectively) and emission wavelengths (650, 653nm) were not substantially different. [3H]DPCPX binding studies on CHO-A1 cell membranes showed that XAC-BY630 had a lower affinity for the A1AR than XAC (pKj=7.79±0.13 and 6.S2±0.11, XAC and XAC-BY630, respectively, mean±s.e.mean, n=4). XAC-BY630 also behaved as a competitive ApAR antagonist at both 5'-N-ethylcarboxamidoadenosine-mediated inhibition of cAMP production (apparent pKB=6.9S±0.15 vs. S.06+0.24 for XAC. n=3) and stimulation of inositol phosphate production (apparent pKB=6.26±0.20 vs. 7.46±0.0S for XAC, n=4). Confocal imaging showed that XAC-BY630 bound to membrane-localised ApARs in a time- and concentration-dependent manner. Binding of XAC-BY630 (25-250nM) v/as detected after 5 min, and was predominantly located at the membrane after a 30 min. incubation. Membrane binding of XAC-BY630 was receptor-specific, since a 30 min pre-incubation with DPCPX (10"8-10"°IvO caused a concentration-dependent inhibition of membrane binding (30 min, 50nlvl). These studies indicate that XAC-BY630 is a functional ApAR antagonist with moderate affinity which could be used to visualise the A.pAR in primary tissue and cell lines. Fluorescence Correlation Spectroscopy (FCS). FCS is a non-invasive technique which measures fluctuations in fluorescence intensity in a confocal volume of gives information about the speed of diffusion (i.e. mass) and concentration of the fluorescent molecules present. Thus free ligand (fast diffusing) and bound iigand (slow diffusing) can be quantified simultaneously on a single cell. We have used FCS to measure binding of the fluorescent ligand, xanthine amine cogener- BODEPY®630/650 (XAC-BY630) to the human adenosine A, receptor (ApAR). CHO cells expressing either the human ApAR or an ApAR-Topaz fusion were cultured on glass-bottomed S-well plates and prepared for live cell measurement . FCS measurements were made using a Zeiss Confocor 2, fitted with an Axiocam CCD camera for x-y positioning. Cells were incubated with ligands at 22°C for the times indicated and the confocal volume was positioned on the upper membrane. Data were collected for 2x30s, following a 15s pre-bleach and analysed using a multi-parameter equation using Zeiss AIM software. Initially, the diffusion characteristics of the A1-AR-Topaz fusion protein (A1-AR- Tpz) were detennined in CHO-AlTpz cells. Autocorrelation analysis showed the diffusion time (ιD) for the ArAR was 15.0±0.9ms (meanls.e.mean, n=84). A second component (xD=118±14}is) was also seen, probably caused by an optical event within the fluorophore ('blinking"). FCS analysis of XAC-BY630 in buffer showed a single component diffusion (TD=60±2US, n=10). On the upper membrane of CHO-A1 cells incubated with XAC-BY630 (l-40nM, 10-60 min, n=71), two further slow-diffusing species were detected in addition to free ligand. The first component had a similar diffusion time (ιD1=17.4±l.lms; 69/71 cells) to that seen for ApAR-Tpz, suggesting that it is receptor-bound ligand. The second was a very slow diffusing component (ιD2=345±41ms, 61/71 cells). Following preincubation with 8-cyclopentyl-l,3-dipropyl xanthine (DPCPX) (1µ-M, 30 min), tD2 was present in 30/31 cells, suggesting this component is non-specific binding. However, the tpi component was present in only 17/31 cells. In addition, in cells exposed to 15nM XAC-BY630 for 30 min the amount of TDI component was reduced from 51.8±14.9 to 13.6±5.4 receptors/urn" by DPCPX (n=8 and 4, respectively, Student's t-test, PO.05), further suggesting this component is ApAR bound ligand. We have used FCS to quantify binding to the ApAR and measure receptor diffusion in single live cells. Further development allows quantitative receptor-ligand binding of the endogenous ApAR in acutely dispersed cells. These studies indicate that XAC-BY630 is a functional ApAR antagonist with moderate affinity which could be used to visualise and measure binding to the Ap AR, in primary tissue and cell lines. Extample B2-Einding of NEC A based fluorescent A1-receptor wonists 2. BY630-ABEA (3) Functional studies were performed in CHO-K1 cells expressing both the human Ap AR and a c-fos-pGL3 reporter vector (CHO-Alfos cells). Cells were incubated for 24h in serum-free DMEM/F-12 media, men stimulated with agonist for 5h, in some cases following 30 min incubation with 8-cyclopentyl-l,3-dipropyLxanthine (DPCPX). Luciferase expression was quantified using a Luclite15 kit according to manufacturer's instructions. Live cell confocal imaging was carried out on CHO-A1 cells or CHO cells expressing the ApAR tagged on the C-terminus with a green fluorescent protein (CHO-A1Tpz). In CHO-Alfos cells, both BY630-ABEA and the ApAR agonist N6-cyclopentyl adenosine (CPA) stimulated luciferase expression in a dose-dependent manner (pEC50's of 7.0I±0.04 (n=6) and 6.76±0.1S (n=5) for CPA and BY630-ABEA, respectively, mean±s.e.mean). Stimulation was mediated by the ApAR receptor, since the concentration response curves were shifted to the right in a competitive maimer by 10nM DPCPX, yielding pKd values of 8.72±0.03 and 9.05±0.10 vs. CPA and BY630-ABEA, respectively (n=3). A higher dose of DPCPX (100nM), gave a pKd of 8.62±0.02 for CPA stimulation, but completely blocked the response to BY630-ABEA (n=3). For receptor visualisation, CHO-A] cells were incubated with 100nM BY630-ABEA for up to 60min. Binding of ligand to the membrane was detectable after 5 min, and was substantial after 30 min (n=3). Binding was to the A1-AR, since it was substantially reduced by preincubation with DPCPX (lµM, 30 min). In addition, experiments in CHO-A1Tpz cells, showed co-localisation of ligand fluorescence at the membrane with that from the fluorescently tagged A1-AR. Results are shown in Figure 1 which shows images taken from confocal microscopy imaging of a) fluorescence derived from ligand binding of a fluorescent ligand of the invention to CHO cells observed at the red channel, b) fluorescence derived from green fluorescent protein expressed by CHO cells indicating receptor locations observed via the green channel and c) overlaid images from a) and b) showing overlap of fluorescence and therefore confirming ligand binding is specific to receptors. In conclusion, we have succeeded in synthesising a novel fluorescent agonist ligand for the human A1-AR. This ligand will be useful in monitoring the localisation of the endogenous Ai-AR receptor in both acutely dispersed cells and cell lines. C. LIGANDS ASSOCIATED WITH PHARMACOLOGICAL DATA Example CI - Data sheets for library / catalogue compound comprizing adenosine based fluorescent Ay-receptor antagonists 1. XAC-BY630 (1) Characterisation: Fluorescent adenosine A1-receptor antagonist. Synthesis and analysis: see A1 above. Storage....-20°C (dark) Spectral Properties: Excitation Max 63Snm Emission Max 655nm Fluorescence Lifetime 4.2 ns Emission quantum yield 0.33 Pharmacology: CHO-cells expressing human adenosine A1-receptor: Inhibition of 3H-DPCPX binding (membranes) pKB = - 6.82 + 0.11 Inhibition of 3H-DPCPX binding (whole cells) pKB = -6.9 Antagonism of NECA-stimulated cAMP accumulation pK1 = -6.9S + 0.15 Antagonism of NECA-stimulated inositol phosphate accumulation pK[ = -6.26 + 0.20 Imaging;: Picture of XAC-BY630/650 binding to CH0-A1 cells and CHO-A1-GFP cells Also pictures showing displacement of binding by non-fluorescent antagonist DPCPX. Example D LIBRARY WITH DIFFERENT FLUORESCENTLY TAGGED LIGANDS Dl A library is assembled comprising 3 fluorescent ligands each ligand comprising ABIPEA fluorescently tagged with a fluorophore providing different fluorescence characteristics selected from BODIPY 630/650-X-SE, EvoBlue 30 SE, BODIPY FL ethylene diamine etc. Fluorescently tagged ligands are obtained by the process of the invention as hereinbefore defined. The library includes data sheets (C. above) for each ligand. D2 An alternative library is assembled comprising 2 fluorescent ligands comprising adenosine and ABIPEA as herein before referred, each were divided into 3 samples and modified by incorporation of a linker of varying carbon chain length from C3-6. whereby the compounds of formula IV comprised JL is amine. L is (CH2)3. 0 and YL is amine. The compounds were reacted with fluorophore providing different fluorescence characteristics selected from EvoBlue 30 SE and BODEPY 630/650 X- SE. Fluorescently tagged ligands are obtained by the process of the invention as hereinbefore defined. The library includes data sheets (C. above) for each ligand. D3 An alternative library is assembled comprising 3 tagged ligands each ligand comprising ABIPEA tagged with a selection of tags as known in the art, including one tagged with a fluorophore. The library includes data sheets (C. above) for each ligand. The libraries are useful for conducting binding studies as known in the art for a desired" fluorescent ligand having the desired fluorophore or for a selection of fluorescent ligands or for a selection of ligands one of which comprises a desired fluorophore. A library was then selected for screening for binding at a desired receptor and a fluorescent ligand was selected which gave optimum pharmacology for the desired receptor. Choice of the library to be screened is facilitated by the rational design of the library which provides the required analogues to generate a positive selection. We Claim: 1. Library comprising a plurality of tagged ligands of formula 1 (LigJL)m L (JT Tag) m (JT L (JL Lig)m)p and salts thereof wherein any optically active ligand is present as a racemate or as one of its optically active isomers comprising ligand moiety Lig linked to tag moiety Tag via linker moiety L at linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter; L is selected from a single or double bond, -0-, -S-, amine, COO-, amide, -NN- hydrazine; and saturated or unsaturated, substituted or unsubstituted C1-600 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, wherein optional substituents are selected from any C1-20 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano and carbonyl and combinations thereof, and L may be monomeric, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300; m arc each independently selected from a whole number integer from 1 to 3; p is 0 to 3 wherein one or more or each -Tag in each library compound is a fluorophore entity - F1, whereby the library comprises compounds of formula I' (LigJ,)m L (JT Fl)m (JT L (J1Lig)m)p wherein linking is at same or different linking sites in compounds comprising different Lig, J;, L Jr and/or - Tag and is at different linking sites in compounds comprising same Lig, JL, L JT and/or - Tag characterised in that the or each Fl is selected from a red, near ir or blue dye. 2. Library comprising a plurality of tagged ligands of formula I (Lig JL)m L (JT Tag) m (JT L (JL Lig)m)p and salts thereof wherein any optically active ligand is present as a racemate or as one of its optically active isomers comprising ligand moiety Lig linked to tag moiety Tag via linker moiety L at linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter; 1. is selected from a single or double bond. -O-, -S-, amine, COO-, amide, -NN- hydrazine; and saturated or unsaturated, substituted or unsubstituted C1-600 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, wherein optional substituents are selected from any C1-20 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano and carbonyl and combinations thereof, and L may be monomeric, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300; m are each independently selected from a whole number integer from 1 to 3; p is 0 to 3 wherein one or more or each -Tag in each library compound is a fluorophore entity - F1, whereby the library comprises compounds of formula I' (LigJL)m L(JTFl)m(JTL(JLLig)m)p wherein linking is at same or different linking sites in compounds comprising different Lig, Jl., L JT and/or - Tag and is at different linking sites in compounds comprising same Lig, JL, L JT and/or - Tag characterised in that the or each Fl is selected from the following dyes: Texas red™, coumarin and derivatives, Cascade Blue™, EvoBlue and fluorescent derivatives thereof, pyrenes and pyridyloxazole derivatives, the cyanine dyes, the dyomics (DY dyes and ATTO dyes) and fluorescent derivatives thereof, the Alexafluor dyes and derivatives, BDI dyes including the commercially available Bodipy™ dyes, pyrenes, anthracenes, acridines, fluorescent phycobiliproteins and their conjugates and fluoresceinated microbeads, and Texas Red derivatives, coupled to amine groups using the isocyanate, succinimidyl ester or dichlorotriazinyl-reactive groups. 3. Library as claimed in Claim 1 or 2 wherein Fl is of formula JT - t - F1 and comprises a BODIPY ™ structure characterised by a dipyrrometheneboron difluoride core, optionally modified by one or two fused rings, optionally substituted by one or several substituents selected from alkyl, alkoxy, aryl or heterocyclic, wherein one substituent -t- is adapted for linking as hereinbefore defined to a ligand precursor as hereinbefore defined, wherein the substituent -t- comprises a proximal unsaturated or aryl moiety, comprising a medial short, medium or long chain alkynyl or cycloalkyl moiety and comprising a moiety derived from linking via a reactive group as hereinbefore defined or selected from carboxyl, sulphonate or as a heteroatom O or S or methylene derived from linking at an alkylhalide including methylbromide, haloacetamide or sulphonate ester electrophilic group. 4. Library as claimed in any of the preceding Claims wherein the or each Fl is selected from Texas Red ™, Cy5.5 or Cy5 or analogues thereof, DY-630, DY-640, DY-650 or DY-655 or analogues thereof, ATTO 655 or ATTO 680 or analogues thereof, EvoBlue 30 or analogues thereof, Alexa 647 or analogues thereof, BODIPY® 630/650 and analogues thereof including BODIPY® 630/650 X. 5 Library as claimed in any of Claims 1 to 4 wherein each compound of formula I or L comprises one of a plurality of fluorophores and/or tags providing a library of differently fluorescently tagged ligands comprising one or a number of different lluorophores of same or different chemical composition or spectral characteristics; and/or providing a library of differently tagged ligands including at least one fluorescently tagged ligand; or each compound of formula I or I' comprises one of a plurality of precursor ligands linked each to one or a plurality of different tags providing a library of same or differently tagged ligands of plural ligand type; or each wherein each JL and JT comprises J as hereinbefore defined and may be same or different and may derive from functionality originally present in Lig or L and Tag or L or a combination thereof, characterised in that linking is at same or different linking sites in compounds comprising different Lig, JL, L, JT and/or Tag, and is at different linking sites in the case of any two or more compounds comprising identical Lig, JL, L, JT and/or Tag. 7. Library as claimed in any of Claims 1 to 6 including information for each compound of formula I comprised in the Library, relating to the pharmacology for binding to or inhibition of a GPCR receptor or to inhibition of an intracellular cyclic nucleotide phosphodiesterase, or inhibition of or transport by a drug transporter including designation as agonist, antagonist, substrate or inhibitor and measure of affinity or inhibition, enabling quantification of results. 8. Library as claimed in any of Claims 1 to 7 wherein a GPCR ligand is selected from any compound which is effective as an agonist or antagonist for an adenosine receptor, a beta-adrenoceptor, a muscarinic receptor, a histamine receptor, an opiate receptor, a cannabinoid receptor, a chemokine receptor, an alpha-adrenoceptor, a GABA receptor, a prostanoid receptor, a 5-HT (serotonin) receptor, an excitatory aminoacid receptor (glutamate), a dopamine receptor, a protease-activating receptor, a neurokinin receptor, an angiotensin receptor, an oxytocin receptor, a leukotriene receptor, a nucleotide receptor (purines and pyrimidines), a calcium-sensing receptor, a thyroid-stimulating hormone receptor, a neurotensin receptor, a vasopressin receptor, an olfactory receptor, a nucleobase receptor (adenosine), a lysophosphatidic acid receptor, a sphingolipid receptor, a tyramine receptor (trace amines), a free-fatty acid receptor and a cyclic nucleotide receptor; an inhibitor of intracellular enzymes is an inhibitor of cyclic nucleotide phosphodiesterases; and a substrate or inhibitor of a drug transporter is selected from a substrate or inhibitor of an equilibrium based drug transporter or ATP driven pump selected from a catecholamine transporter, a nucleoside transporter, an ATP-binding cassette transporter, a cyclic nucleotide transporter or derivatives or analogues thereof; or wherein Lig is selected from a) xanthine like structures including XAC, theophylline, caffeine, theobromine, dyphilline, enprofylline; or fused biaryl structures including papaverine, dihydroquinilones, cilostamide, dipyridamole or vinpocetine; and analogues thereof; b) adenosine like structures including ADAC, NECA and analogues thereof; c) ethanolamine like structures including salmeterol, salbutamol, terbutaline, quinprenaline, labetalol, sotalol, bambuterol, fenoterol, reprotolol, tulobuterol, clenbuterol and analogues thereof; d) oxypropanolamine like structures including CGP12177, propranolol, practolol, acebutalol, betaxolol, ICI 118551, alprenolol, celiprolol (celectol), metoprolol (betaloc), CGP20712A, atenolol, bisoprolol, misaprolol, carvedilol, bucindolol, esmolol, nadolol, nebivolol, oxprenolol, xamoterol, pindolol, timolol and analogues thereof; e) xanthine like structures including XAC, theophylline, caffeine, theobromine, dyphilline, enprofylline, sildenafil, EHNA (erythro-9-(2-hydroxyl-3-nonyl)adenine), zaprinast; or spiro bicyclic structures including bypyridines, amrinone; imidazolines, CI930; dihydropyridazinones, indolan, rolipram, SB207499; or fused biaryl structures including papaverine, dihydroquinilones, cilostamide, dipyridamole, vinpocetine and analogues thereof. 9. Library as claimed in any of Claims 1 to 8 wherein JLm L JTm comprises a mono, di, tri, tetra, penta, or hexa amino, alkylthio, alkoxy, carboxylic acid, and combinations thereof including a mono, di or tri aminoalkylthio, amino alkoxy, alkoxy carboxylic acid or alkoxy amine, mono, di or tri amino menthane, amino ethane, thio ethane, ethane, amino acyl, polypeptide, or mono or polyether derivatives including diamine or dithio derivatives, mono or polyethylene glycol di or tri amine or thio; or comprises a mono-, di-, tri- or tetra, penta or hexafunctional linear or branched or cyclic substituted or unsubstituted hydrocarbyl of formula -L.I- J [ A ] q,. RL [ A'q,.--P ]PA"qL-J" wherein each of J to J" is a linking site or functionality as hereinbefore defined independently selected from a single or double bond, methylene, alkyne, alkene, NR, (). CONR, NRCO, S, CO, NCO, CHHal and P wherein R is H or C1-8 alkyl or cycloalkyl or forms part of a cyclic ring with N, Hal is any halogen selected from chlorine, iodine, bromine; and is present in any rational location in a group A to A"; each of A to A " is a group selected from -O-, -C(=O)-, C1-2 alkoxy, alkoyl, cycloalkyl, heterocyclic, alkyl, alkenyl, aryl, arylamide, arylamine, amino, thioalkyl, heteroaryl as hereinbefore defined and combinations thereof, optionally substituted by groups selected independently from C1-3 alkyl and C1-5 alkoxy; each of qL to qL" are independently-selected from 0 or 1 or indicates an oligomeric repeat and is from 2 to 30, or indicates a polymeric repeat unit and is from 31 up to 300. R1. is a C, N or S atom or is a CRL, NRL , alkyl, cycloalkyl, heterocyclic, aryl heteroaryl, amine or thio moiety and provides for branching when p is 1 or 2; wherein R1. is H or C1-3 alkyl; and p is as hereinbefore defined and is 0, 1 or 2. 10. Library as claimed in any of Claims 1 to 9 wherein JL-m L JTm is of formula J AqL R,.J" wherein each of J and J" is amine or-O-, A is CH2CH2O, qL is 1-30 or 31 to 300 and R1. is CH2CH2 or of formula J AqL RL(A'J') J" wherein each of J, J' and J" independently is amine, -O or a single bond, qL is 1, 2 or 3 -30 or 31 to 300 and A is CH2CH2O or HNCH2CO or qL is 1 and A is C(O) or (CH2)1-8 or qL is 0, RL is CH or CH2CH, qL- is 0 or qL' is 1 and A' is CH2 and qL is 0 preferably 0(CH2CH2O)ql.CH2CH2NH, O(CH2CH2O)qLCH2CH(CH2NH)NH, OCH(CH2NH)NH, -CH(CH2NH)NH, -C(O) NH-, -(CH2)1-8- or (-HNCH2CO-)1-3 (= - gly1-3-)- 11. Library as claimed in any of Claims 1 to 10 wherein each compound of formula 1 or I' comprises a moiety Lig and L as hereinbelow defined: Wherein: any optically active fluorescent ligand is present as a racemate or as one of its optically active isomers Lig.am is suitably of the formula, in either of the following forms given, including any of its possible linking configurations or sites: Lig.a 'm Wherein at least one or all of Ra1 to Ra4, X1 and X2 comprise a linking site or functionality J as hereinbefore defined X1 and X2 are each independently selected from H, O, OR.a, NR.a, NHR.a; each of R.a', R.a2, R.a3 and R.a4 independently is selected from H or C1-4 linear or branched alkyl optionally mono or multi hydroxy or halo substituted; R.a4 is selected from a heteroatom O, S or substituted or unsubstituted amine or saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo and cyano; including substituted or unsubstituted aryl, cycloalkyl, alkyl, ketone, (di)amine, (di)amide, alkoxy, cycloalkyl, carboxylic acid or optionally o-, m- or p- substituted phenyl wherein substituents include aryl, alkyl, cycloalkyl, heteroaryl or heteroalkyl, amine, amide, carboxyl, carbonyl or R.a4 comprises cyclohexyl, cyclopentyl, ethoxy, (CH2)2PhPh, CH2Ph, CONH(CH2)nCONH, CH2CONH(CH2)2NH, CH2PhNHCOCH2, CH2CH2OCOCH2, succinimidyl ester, NHCOCH2, CH2(CH3)NCOCH2, H2N(CH2)2NHCOCH2, H2N(CH2)8NHCOCH2, H2NNHCOCH2, CH2CONH(CH2)2NHCOCH2) HOPhCH2N(CH2CH3.HOAc)(CH2)2NHCOCH2. heterocyclic-(CH2)4CONH(CH2)2NHCOCH2or heterocyclic-NHCON(heterocyclic)COCH2; wherein at least one or all of Ra5 to Ra6, or a cyclic C or heteroatom comprise a linking site or functionality J as hereinbefore defined, each of C.Ai and C.A2 is independently selected from C5.6 aryl, heteroaryl, cycloalkyl and heterocyclic, or from phenyl, or aryl containing 1 or 2 ring heteroatoms, or heterocyclic containing 1 ring heteroatom and/or I ring -C=C- group; Kach of up to seven R.a5 is a substituent of a ring carbon or a ring heteroatom and: is independently selected from H, halo, hydroxy, thiol, amine, COOH, hydrazine, cyano, saturated or unsaturated, substituted or unsubstituted Ci.2o branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, and wherein substituents are selected from any C|.|2 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo =0 or cyano; OCH3, CH2Ph(OCH3)2, 0(CH2)3CON(CH3)c.hex, N(CH2CH2OH)2, c.hex, COOCH2CH3, CH2CH3; or any two or more of R.a5 form a one, two or three ring fused cyclic structure, a fused 3 ring aryl, 5-heterocyclic or 6-heterocyclic structure having 4 ring atoms common with the fused bicyclic Lig.a2structure; and R.a6 is a moiety as defined for R.a5 above; and L.a is as hereinbefore defined for L or JL L Jr or L.l or subformulae as hereinbefore defined, or is a single bond, amino acid or amide including a peptide or polypeptide gly or gly3, alkyl of formula -(CH2)n where n is 3 to 8, optionally including one or more heteroatoms or unsaturated groups, including -O- or -S- or - CH-CH-: L.ig.b is suitably of the formula Lig.b including any of its possible linking configurations or sites: wherein at least one or all of Rb1 to Rb5 or Xb1 to Xb3 comprise a linking site or functionality J as hereinbefore defined ring substituents X.b1 and X.b2 are independently selected from hydrocarbon including alkyl or SRx, NRX2 and ORx wherein (each) Rx is selected from H, Ci.5alkyl, alkenyl; ring heteroatom X.b3 is selected from -S-, -O- and -CH2-; Rb1 is selected from saturated or unsaturated, substituted or unsubstituted C1-4 aliphatic, or C1-3 alicyclic which may include one or more heteroatoms N, O, S, P, wherein substituent(s) are selected from one or more cycloalkyl, heterocyclic, hydroxy, oxo, halo, amine; or R.b comprises a carbonyl substituted by H, alkyl or a linear or cyclic primary, secondary or tertiary amine, substituted C1-3 alkyl, cycloalkyl or amide, cyclopropyl, or CONHC1-3alkyl including CONHEt or CH2OH and each of R.b2 and R.b3 is selected from H, halo, hydroxy, thiol, amine, COOH, CHO, hydrazine, cyano or saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo or cyano, preferably from H, halo or hydroxy; Rb4 is H; Rb5 is H or alkyl L.b comprises a linking site or functionality J as hereinbefore defined; and is as hereinbefore defined for L or its subformulae, or is saturated and unsaturated substituted or unsubstituted C1-12 aliphatic or C1-24 aromatic as defined for L which may include one or more heteroatoms O, S or N, cyclic or heterocyclic groups, or is of formula L.I or its subformulae as hereinbefore defined, or is ( CH2)m wherein m is 2 to 12, or is (Ph- CH2CONH)2 (CH2)2; Lig.c is of the formula Lig.c including any of its possible linking configurations or sites: where at least one or all of Rc1 to Rc2 or OH, or a chain C or N comprise a linking site or functionality J as hereinbefore defined * indicates an optically active centre and wherein R.c1 is C6-14 substituted or unsubstituted aryl which may include one or more heteroatoms selected from H, O, wherein substituents are selected from OH, Hal, NH2, NHC1-3alkyl, sulphonamide, oxoamine or (-CONH2), or is mono, di or tri substituted phenyl or quinoline wherein substituents include OH, Cl or NH2, or is m-CH2OH, p-OH phenyl, m-,p-dihydroxy phenol or m-,m-dihydroxyphenol, m-,m-diCl, p-NH2 phenol, p-OH, m- CONH2 phenol or 5-OH, 8-quinoline, R.c2 is selected from saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P; wherein optional substituents are selected from any substituted or unsubstituted C1-2 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo or cyano and combinations thereof; or R.c2 is selected from C1-6 branched or straight chain aliphatic, C6-10 araliphatic optionally substituted by OH and optionally including heteroatoms selected from N,0, optionally including an ether O, and is selected from -(CH2)6OCH((CH2)3Ph), CHCH3(CH2)2Ph, CHCH3CH2PhOH, C(CH3)2CH2 or from the structures: where at least one or all of Rd1 to Rd2 or OH, a chain C or N comprise a each X is independently selected from H, O, -OR.e2, N, HN, NR.e5, HR.e6 , and aryl unsubstituted or substituted by ether; or X is aryl unsubstituted or alkyl or alkoxy substituted or is Ph-ortho- OCH2CH2CH3; and where R.e5 is as defined above for R.e1 above or forms a fused cyclic ring together with the adjacent ring N atom, or 1 or 2 fused 5 membered cyclic rings; and R.e6 is as defined above for R.e1 above or is selected from unsubstituted or substituted phenyl wherein substituents include ether, o-ethoxy or o-propoxy, alkyl or OH, sulphonyl or carbonyl substituted by heterocyclic, or cyclic C5-8 alkyl, piperazinyl or sulphonyl; wherein at least one or all of Re" to Re12, or a ring C or heteroatom or ring substituent comprise a linking site or functionality J as hereinbefore defined each of C.ni and C.E2 is independently selected from C5-6 aryl, heteroaryl, cyloalkyl and heterocyclic, including phenyl, or aryl containing 1 or 2 ring heteroatoms, or heterocyclic containing 1 ring heteroatom and/or 1 ring -C=C- group; each of up to seven R.e" is a substituent of a ring carbon or a ring heteroatom and: is independently selected from saturated or unsaturated, substituted or unsubstituted C1-20 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, and wherein optional substituents are selected from any C1-12 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo =O, or cyano, OCH3, CH2Ph(OCH3)2, O(CH2)3CON(CH3)c.hex, N(CH2CH2OH)2, c.hex, COOCH2CH3, CH2CH3; or any two or more of R.e" form a one, two or three ring fused cyclic structure, a fused 3 ring aryl, 5-heterocyclic or 6-heterocyclic structure having 4 ring atoms common with the fused bicyclic Lig.e3 structure; and R.e12 is a moiety as defined for R.e11 above; L.e comprises a linking site or functionality J as hereinbefore defined and is suitably as hereinbefore defined for L.a. 12. Library as claimed in Claim 11 wherein: Lig.a is of the formula, in either of the following forms given, including any of its possible linking configurations or sites: wherein Ra4 comprises linking functionality Jwhich is amine; X1 and X2 are each O; R.a3 is H; each of R.a' and R.a2 is n-propyl; R.a is p- substituted phenyl wherein the substituent includes heteroalkyl, amide and amine; and L is of formula L.I or is a single bond or alkyl of formula - (CH2)n where n is 3 to 8, preferably 3, 4 or 6, which may include one or more heteroatoms -O; Lig.b is of the formula Lig.b including any of its possible linking configurations and sites: wherein ring substituents X.b' and X.b2 are each OH; ring heteroatom X.b3 is -O-; Rb1 is CONHEt or CH2OH; and each of R.b2 and R.b3 is H; Rb4 is H; Rb5 comprises linking functionality J which is amino, and linker L.b selected from saturated C1-12 aliphatic and C6-24 aromatic, unsubstituted or substituted by one or more C1 alkyl and which may include one or more heteroatoms O or cyclic groups; Lig.c is of the formula Lig.c including any of its possible linking configurations or sites: as a racemate or as one of its optically active isomers wherein * indicates an optically active centre, Re1 is m-, p- dihydroxyphenyl; and Re2 comprises linking functionality J which is amine, and linker L.c which is selected from C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof which may comprise one or more heteroatoms O and optionally substituted by C1 aliphatic; or Lig.d is a non-peptide of the formula Lig.d including any of its possible linking configurations or sites: and a C1-20 aromatic comprising one or more heteroatoms selected from N, O, S, P and unsubstituted or halo substituted; and Rd2 comprises linking functionality J which is amine, and linker L.d which is selected from C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof which may comprise one or more heteroatoms O and unsubstituted or substituted by C1 aliphatic; or Rd2 is C1-6 straight chain alkyl including ether O and substituted by C6-10 aryl which is OH and oxo substituted and comprises linker L.d as hereinbefore defined. 13. Library as claimed in claim 12 wherein R.a4, R.b5 or R.c2 or R.d2 comprises linking functionality J, and linker L.a, L.b, L.c or L.d are selected from alkyl of formula (CH2)n or from (CH2)n wherein n is 3, 4, 6 or 8 or is in the range 3 to 8 or 2 to 12 or is C1-12 alkyl optionally including one or more heteroatoms O or L.a is a single bond; or R.c2 or R.d2 comprises linking functionality Jas hereinbefore defined, and linker L.c or L.d and is selected from C1-12 branched aliphatic or aromatic and combinations thereof or C6-10 araliphatic such as selected from C(CH3)2CH2Ph and the structure Alprenolol-BY630/650 15 . A library of fluorescent ligands of formula I or V as claimed in any of claims 1 to 14 wherein a ligand is an agonist(s) which maintains its binding affinity and its functional activity or is an antagonist which maintains its binding affinity on linking or when linked to fluorescent moiety Fl. 16. A library of fluorescent ligands of formula I or V as claimed in Claim 15 wherein fluorescent ligand(s) has affinity such that it binds permanently, semi- permanently or transiently and remains bound when unbound ligand is washed away. 17 . Process for the preparation of a library as claimed in any of Claims 1 to 16 which is a combinatorial process; and comprises the reaction of one or more ligand precursors of formula IV and/or IV IV (LigJl.) m-L-YLm IV Lig YLigm comprising one or more or different reactive groups Yl. or YL,g forming a linking functionality J, JL or JT as hereinbefore defined with one or more of a plurality of analytical tagging substrates of formula V and/or V V YTm Tag V Ylm L (JTTag) m comprising one or more or different reactive groups Yj forming a linking functionality J or J r as hereinbefore defined and optionally one or more linking species VI VI YLmL YLm wherein Lig, J, L, JT and Tag and each m is independently as hereinbefore defined wherein the or each compound of formula IV or IV is capable of reaction with the or each compound of formula V or V, which reaction may be via the or each species VI or VI' or VI" to form a plurality of compounds of formula I as hereinbefore defined. 18. Process for the preparation of a compound of formula IV as hereinbefore defined in Claim 17 comprising: obtaining where commercially available or preparing the ligand precursor Lig, by routes as known in the art, and reacting with linker precursor VI", if required, or components thereof, and/or generating one or more reactive sites Y or YLig or YL, by a method selected from: a), e) ring closure of 5,6-diamino-l,3-dialkyl uracil with the appropriate substituted aldehyde under acid conditions with ferric chloride, b) reacting Lig.b- comprising a protected inosine derivative with chlorinating agent and linking the chloro derivative with the amine group of a protected amine reactive linker H-L-P1 wherein Pl comprises N-benzyloxycarbonyl- to form Lig.b -L-Pi. and removing Pl to generate Lig.b -L.b; c), d) reacting p-hydroxybenzaldehyde with formaldehyde under acid catalysis and protection of the resulting 4-hydroxy-3- hydroxymethylbenzaldehyde with dimethoxypropane to generate the resulting acetonide, converting the Benzaldehyde to its corresponding epoxide and ring opening with a protected linker such as Boc-L.c-H supplies Ligm-L-Pu finally, deprotection under acid conditions supplies Lig.cLc or Lig.dLd for coupling to an appropriate tag. 19. Process as claimed in Claim 17, comprising additionally determining pharmacology for a plurality of or all compounds in the library in order to enable selecting a compound exhibiting desired pharmacology. 20. Process as claimed in Claim 18 or 19 which comprises preparing a preliminary library of compounds, conducting screens to assess binding or inhibition, selecting a compound identified in the screen as having beneficial properties, and modifying or functionalising by nature of moieties or linking location of linking on the basis of the indications from the screen to prepare an optimised library, wherein the molecular pharmacology and photochemistry from the screen feedback into the design of the library. 21. Compound comprising a tagged ligand of formula I (Lig J|.)m L (JT Tag) m (JT L (JL Lig)m)p and salts thereof wherein an optically active ligand is present as a racemate or as one of its optically active isomers comprising ligand moiety Lig linked to tag moiety Tag via linker moiety L at linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter; L is selected from a single or double bond, -O-, -S-, amine, COO-. amide, -NN- hydrazine; and saturated or unsaturated, substituted or unsubstituted C1-600 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, wherein optional substituents are selected from any C1-20 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano and carbonyl and combinations thereof, and L may be monomeric, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300; m are each independently selected from a whole number integer from 1 to 3; p is 0 to 3 wherein -Tag is a fluorophore entity-Fl, whereby the compound is of formula 1' (LigJL)m L(JTFI)m(JTL(JLLig)m)p characterised in that Fl is selected from a red, near ir or blue dye. 22. Compound comprising a tagged ligand of formula I (Lig JL)m L (JT Tag) m(JT L (JL Lig)m)p and salts thereof wherein an optically active ligand is present as a racemate or as one of its optically active isomers comprising ligand moiety Lig linked to tag moiety Tag via linker moiety L at linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter; L is selected from a single or double bond, -O-, -S-, amine, COO-, amide, -NN- hydrazine; and saturated or unsaturated, substituted or unsubstituted C1-600 branched or straight chain aliphatic, aromatic, alicyclic and combinations thereof, any of which may comprise one or more heteroatoms selected from N, O, S, P, wherein optional substituents are selected from any C1-20 aliphatic, aromatic or alicyclic substituents any of which may comprise one or more heteroatoms as hereinbefore defined, hydroxy, thiol, halo, amine, hydrazine, oxo, cyano and carbonyl and combinations thereof, and L may be monomeric, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300; are each independently selected from a whole number integer from 1 to 3; is 0 to 3 wherein -Tag is a fluorophore entity -Fl, whereby the compound is of formula I' (LigJOm L (J, FI)m(J, L(J,.Lig)m)p characterised in that Fl is selected from the following dyes: Texas red™, coumarin and derivatives, Cascade Blue™, EvoBlue and fluorescent derivatives thereof, pyrenes and pyridyloxazole derivatives, the cyanine dyes, the dyomics (DY dyes and ATTO dyes) and fluorescent derivatives thereof, the Alexafluor dyes and derivatives, BDI dyes including the commercially available Bodipy™ dyes, pyrenes, anthracenes, acridines, fluorescent phycobiliproteins and their conjugates and fluoresceinated microbeads, and Texas Red derivatives coupled to amine groups using the isocyanate, succinimidyl ester or dichlorotriazinyl-reactive groups. 23. Compound as claimed in Claim 21 or 22 wherein Fl is of formula Jj - t - Fl and comprises a BODIPY ™ structure characterised by a dipyrrometheneboron difluoride core, optionally modified by one or two fused rings, optionally substituted by one or several substituents selected from alkyl, alkoxy, aryl or heterocyclic, wherein one substituent -t- is adapted for linking as hereinbefore defined to a ligand precursor as hereinbefore defined, wherein the substituent -t- comprises a proximal unsaturated or aryl moiety, comprising a medial short, medium or long chain alkynyl or cycloalkyl moiety and comprising a moiety derived from linking via a reactive group as hereinbefore defined or selected from carboxyl, sulphonate or as a heteroatom O or S or methylene derived from linking at an alkylhalide including methylbromide, haloacetamide or sulphonate ester electrophilic group. 24. Compound as claimed in any of Claims 21 to 23 wherein Fl is selected from Texas Red ™, Cy5.5 or Cy5 or analogues thereof, DY-630, DY-640, DY-650 or DY- 655 or analogues thereof. ATTO 655 or ATTO 680 or analogues thereof, EvoBlue 30 or analogues thereof, Alexa 647 or analogues thereof, BODIPY® 630/650 and analogues thereof including BODIPY® 630/650 X. 25. A compound of formula I (Lig Ji.)m L (J r Tag) m (JT L (JL Lig)m)p or salt thereof as hereinbefore defined in any of Claims 21 to 24 wherein JLm L Tm is as hereinbefore defined in Claim 10 and wherein any optically active fluorescent ligand is present as a racemate or as one of its optically active isomers. wherein Ra4 comprises linking functionality Jwhich is amine; X1 and X2 are each O; R.a3 is H; each of R.a1 and R.a2 is n-propyl; R.a4 is p- substituted phenyl wherein the substituent includes heteroalkyl, amide or amine; and L is of formula L.I or is a single bond or is alkyl of formula - (CH2)n where n is 3 to 8, which may include one or more heteroatoms -O; Lig.b is of formula Lig.b including any of its possible linking configurations or sites: and a C1-20 aromatic comprising one or more heteroatoms selected from N, O, S, P and unsubstituted or halo substituted; and Rd2 comprises linking functionality J, and linker L.d which is selected from C1-12 straight chain alkyl, C6-12 cycloalkyl or aryl and combinations thereof which may comprise one or more heteroatoms O and optionally substituted by C1 aliphatic; or Rd2 is C1-6 straight chain alkyl including ether O and substituted by C6-10 aryl which is OH and oxo substituted and comprises linker L.d as hereinbefore defined. 30. Compound as claimed in Claim 29 wherein R.a4, R.b5 or R.c2 or R.d2 comprises linking functionality J as hereinbefore defined, and linker L.a, L.b, L.c or L.d are selected from alkyl of formula (CH2)n wherein n is 3, 4, 6 or 8 or is in the range 3 to 8 or 2 to 12 or is C1-12 alkyl optionally including one or more heteroatoms O or L.a is a single bond; or R.c2 or R.d2 comprises linking functionality J as hereinbefore defined, and linker L.c or L.d and is selected from C1-12 branched aliphatic or aromatic and combinations thereof or C6-10 araliphatic such as selected from C(CH3)2CH2 and the structure ABEA-BY630. 32. A compound of formula I or I' as hereinbefore defined in any of Claims 21 to 31 associated with information relating to its pharmacological properties in the form of Spectral Properties given as Excitation Max and Emission Max, Fluorescence Lifetime and Emission quantum yield and Pharmacology defined in terms of cells expressing a GPCR receptor as hereinbefore defined or expressing an intracellular cyclic nucleotide phosphodiesterase, or a drug transporter as hereinbefore defined and given as the Inhibition or Antagonism of receptor binding or of receptor functionality together with a value for the Inhibition (pKs) or Antagonism (pK1) binding constants, and which may be associated with fluorescent images of the pharmacological binding in single living cells illustrating the defined inhibition or antagonism, preferably the pharmacological properties are given as EC50 values for agonist stimulated - or pKj values for antagonism of agonist stimulated second messenger generation, or substrate Km values or antagonist K, values for stimulation or inhibition of intracellular enzymes or drug transporters. 33. Process for the preparation of a compound of formula I as hereinbefore defined in any of Claims 21 to 32 comprising the reaction of a compound of formula IV or IV and a compound of formula V or V or a compound of V or V and additionally VI, as hereinbefore defined in Claim 17 , by reacting the unprotected primary alkyl amine group of a compound of formula IV with a compound of formula V comprising a reactive succinimidyl ester group in solvent at ambient temperature without the need for subsequent deprotection. 34. A kit comprising a library or a compound of formula I or I' as claimed in any of Claims 1 to 16 or 21 to 32 and a target therefor provided as cell derived material selected from a cell line, expressing a GPCR, intracellular enzyme or drug transporter, membrane containing these proteins derived from such a cell line, solubilised receptor, enzyme or drug transporter or GPCR array from that cell line. 35. Kit as claimed in Claim 34 wherein the cell derived material is provided in one of three forms: (I) from cells expressing a green fluorescent protein tagged receptor, intracellular enzyme or drug transporter; (2) from cells expressing an epitope tag for a commercially available fluorescent antibody or (3) a wild-type protein for which a specific fluorescent antibody is also provided. 36. Kit as claimed in Claim 34 comprising a compound of formula I or I' and a fluorescent antibody to a native protein which can be used in (non-recombinant) cells. 37. Kit as claimed in any of Claims 35 or 36 wherein the spectral characteristics of the compound of formula 1 or I' and fluorescent antibody or green fluorescent protein are selected to allow optimum two-colour cross-correlation fluorescence correlation spectroscopy (single or multiphoton). 38. Compound of formula IV or IV or library thereof as hereinbefore defined in Claim 17, 18 or 33 useful for linking to any suitable tag of formula V or V as hereinbefore defined in Claim 17 39. Fluorophore linker of formula V or library thereof as hereinbefore defined in Claim 17. Dated this the 20th day of September, 2005. Library comprising a plurality of tagged non-peptiede iigands of formula (I): (Lig JL)M L(JT Tag) m (JTL(JLLig)m)p including and salts thereof comprising one or a plurality of same or different ligand moieties Lig each linked to a one or a plurality of same or different tag moieties Tag via same or different linker moieties L and same or different linking site or linking functionality JT and JL wherein Lig comprises a GPCR ligand, an inhibitor of an intracellular enzyme or a substrate or inhibitor of a drug transporter; L is a single bond or is any linking moiety selected from a heteroatom such N, O, S, P, branched or straight chain saturated or unsaturated, optionally heteroatom containing, C1-600 hydrocarbyl and combinations thereof, which may be monomeric, oligomeric having oligomeric repeat of 2 to 30 or polymeric having polymeric repeat in excess of 30 up to 300.

Documents:

1873-KOLNP-2005-FORM 27.pdf

1873-kolnp-2005-granted-abstract.pdf

1873-kolnp-2005-granted-assignment.pdf

1873-kolnp-2005-granted-claims.pdf

1873-kolnp-2005-granted-correspondence.pdf

1873-kolnp-2005-granted-description (complete).pdf

1873-kolnp-2005-granted-drawings.pdf

1873-kolnp-2005-granted-examination report.pdf

1873-kolnp-2005-granted-form 1.pdf

1873-kolnp-2005-granted-form 13.pdf

1873-kolnp-2005-granted-form 18.pdf

1873-kolnp-2005-granted-form 2.pdf

1873-kolnp-2005-granted-form 3.pdf

1873-kolnp-2005-granted-form 5.pdf

1873-kolnp-2005-granted-gpa.pdf

1873-kolnp-2005-granted-pa.pdf

1873-kolnp-2005-granted-reply to examination report.pdf

1873-kolnp-2005-granted-specification.pdf

1873-KOLNP-2005.pdf