Title of Invention | "PEPTIDE BASED COMPOUNDS OF GENERAL FORMULA (I)" |
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Abstract | Peptide based compounds of general formula (I) or pharmaceutically acceptable salt thereof wherein G represents glycine D represents aspartic acid Ri represents -(CH2)n- or -(CH2)n-C6H4- wherein n represents a positive integer 1 to 10 h represents a positive integer 1 or 2 Xi represents an amino acid residue wherein said amino acid possesses a functional side-chain such as an acid or amine. X2 and X4 represent independently an amino acid residue capable of forming a disulphide bond, X3 represents arginine, N-methylarginine or an arginine mimetic, X5 represents a hydrophobic amino acid or derivatives thereof, and X6 represents a thiol-containing amino acid residue, and X7 is absent or represents a biomodifier moiety of the kind such as herein described Zi represents an antineoplastic agent, a chelating agent I or a reporter moiety as herein defined and Wi is absent or represents a spacer moiety. |
Full Text | The present invention relates to a peptide based compounds of general formula (I). Field of invention The present invention relates to new peptide-based compounds and their use in therapeutically effective treatments as well as for diagnostic imaging techniques. More specifically the invention relates to the use of such peptide-based compounds as targeting vectors that bind to receptors associated with angiogenesis, in particular integrin receptors, e.g. the av|33 integrin receptor. Such contrast agents may thus be used for diagnosis of for example malignant diseases, heart diseases, endometriosis, inflammation-related diseases, rheumatoid arthritis and Kaposi's sarcoma. Moreover such agents may be used in therapeutic treatment of these diseases. Background of invention New blood vessels can be formed by two different mechanisms: vasculogenesis or angiogenesis. Angiogenesis is the formation of new blood vessels by branching from existing vessels. The primary stimulus for this process may be inadequate supply of nutrients and oxygen (hypoxia) to cells in a tissue. The cells may respond by secreting angiogenic factors, of which there are many; one example, which is frequently referred to, is vascular endothelial growth factor (VEGF). These factors initiate the secretion of proteolytic enzymes that break down the proteins of the basement membrane, as well as inhibitors that limit the action of these potentially harmful enzymes. The other prominent effect of angiogenic factors is to cause endothelial cells to migrate and divide. Endothelial cells that are attached to the basement membrane, which forms a continuous sheet around blood vessels on the contralumenal side, do not undergo mitosis. The combined effect of loss of attachment and signals from the receptors for angiogenic factors is to cause endothelial cells to migrate and divide. Endothelial cells that are attached to the basement membrane, which forms a continuous sheet around blood vessels on the contralumenal side, do not undergo mitosis. The combined effect of loss of attachment and signals from the receptors for angiogenic factors is to cause the endothelial cells to move, multiply, and rearrange themselves, and finally to synthesise a basement membrane around the new vessels. Angiogenesis is prominent in the growth and remodelling of tissues, including wound healing and inflammatory processes. Tumors must initiate angiogenesis when they reach millimetre size in order to keep up their rate of growth. Angiogenesis is accompanied by characteristic changes in endothelial cells and their environment. The surface of these cells is remodelled in preparation for migration, and cryptic structures are exposed where the basement membrane is degraded, in addition to the variety of proteins which are involved in effecting and controlling proteolysis. In the case of tumours, the resulting network of blood vessels is usually disorganised, with the formation of sharp kinks and also arteriovenous shunts. Inhibition of angiogenesis is also considered to be a promising strategy for antitumour therapy. The transformations accompanying angiogenesis are also very promising for diagnosis, an obvious example being malignant disease, but the concept also shows great promise in inflammation and a variety of inflammation-related diseases, including atherosclerosis, the macrophages of early atherosclerotic lesions being potential sources of angiogenic factors. These factors are also involved in re-vascularisation of infarcted parts of the myocardium, which occurs if a stenosis is released within a short time. Further examples of undesired conditions that are associated with neovascularization or angiogenesis, the development or proliferation of new blood vessels are shown below. Reference is also made in this regard to WO 98/47541. Diseases and indications associated with angiogenesis are e.g. different forms of cancer and metastasis, e.g. breast, skin, colorectal, pancreatic, prostate, lung or ovarian cancer. Other diseases and indications are inflammation (e.g. chronic), atherosclerosis, rheumatoid arthritis and gingivitis. Further diseases and indications associated with angiogenesis are arteriovenous alformations, astrocytomas, choriocarcinomas, glioblastomas, gliomas, hemangiomas (childhood, capillary), hepatomas, hyperplastic endometrium, ischemic myocardium, endometriosis, Kaposi sarcoma, macular degeneration, melanoma, rieuroblastomas, occluding peripheral artery disease, osteoarthritis, psoriasis, retinopathy (diabetic, proliferative), scleroderma, seminomas and ulcerative colitis. Angiogenesis involves receptors that are unique to endothelial cells and surrounding tissues. These markers include growth factor receptors such as VEGF and the Integrin family of receptors. Immunohistochemical studies have demonstrated that a variety of integrins perhaps most importantly the av class are expressed on the apical surface of blood vessels [Conforti, G., et al. (1992) Blood 80: 37-446] and are available for targeting by circulating ligands [Pasqualini, R., et al. (1997) Nature Biotechnology 15: 542-546] . The a5(31 is also an important integrin in promoting the assembly of fibronectin matrix and initiating cell attachment to fibronectin. It also plays a crucial role in cell migration [Bauer, J. S., (1992) J. Cell Biol. 116: 477-487] as well as tumour invasion and metastasis [Gehlsen, K. R., (1988) J. Cell Biol. 106: 925-930]. The integrin avp3 is one of the receptors that is known to be associated with angiogenesis. Stimulated endothelial cells appear to rely on this receptor for survival during a critical period of the angiogeneic process, as antagonists of the avp.3 integrin receptor/ligand interaction induce apoptosis and. inhibit blood vessel growth. Integrins are heterodimeric molecules in which the a- and (3-subunits penetrate the cell-membrane lipid bilayer. The a-subunit has four Ca2+ binding domains on its extracellular chain, and the p-subunit has a number of extracellular cysteine-rich domains. Many ligands (eg. fibronectin) involved in cell adhesion contain the tripeptide sequence arginine-glycine-aspartic acid (RGD). The RGD sequence appears to act as a primary recognition site between the ligands presenting this sequence and receptors on the surface of cells. It is generally believed that secondary interactions between the ligand and receptor enhance the specificity of the interaction. These secondary interactions might take place between moieties of the ligand and receptor that are immediately adjacent to the RGD sequence or at sites that are distant from the RGD sequence. RGD peptides are known to bind to a range of integrin receptors and have the potential to regulate a number of cellular events of significant application in the clinical setting. (Ruoslahti, J. Clin. Invest., 87: 1-5 (1991)). Perhaps the most widely studied effect of RGD peptides and mimetics thereof relate to their use as anti-thrombotic agents where they target the platelet integrin GpIIbllla. Inhibition of angiogenesis in tissues by administration of either an av|33 or av(35 antagonist has been described in for example WO 97/06791 and WO 95/25543 using either antibodies or RGD containing peptides. EP 578083 describes a series of mono-cyclic RGD containing peptides and WO 90/14103 claims RGD-antibodies. Haubner et. al. in the J. Nucl. Med. (1999); 40: 1061-1071 describe a new class of tracers for tumour targeting based on monocyclic RGD containing peptides. Biodistribution studies using whole-body autoradiographic imaging revealed however that the 125I-labelled peptides had very fast blood clearance rates and predominantly hepatobiliary excretion routes resulting in high background. Cyclic RGD peptides containing multiple bridges have also been described in WO 98/54347 and WO 95/14714. Peptides derived from in vivo biopanning (WO 97/10507) have been used for a variety of targeting applications. The sequence CDCRGDCFC (RGD-4C), has been used to target drugs such as doxirubicin (WO 98/10795), nucleic acids and adenoviruses to cells (see WO 99/40214, WO 99/39734, WO 98/54347, WO 98/54346, US 5846782). Peptides containing multiple cysteine residues do however suffer from the disadvantage that multiple disulphide isomers can occur. A peptide with 4 cysteine residues such as RGD-4C has the possibility of forming 3 different disulphide folded forms. The isomers will have varying affinity for the integrin receptor as the RGD pharmacophore is forced into 3 different conformations. Further examples of RGD comprising peptide-based compounds are found in PCT/N001/00146 and PCT/N001/00390, the content of which are incorporated herein by reference. The efficient targeting and imaging of integrin receptors associated with angiogenesis in vivo demands therefore a selective, high affinity RGD based vector that is chemically robust and stable. Furthermore, the route of excretion is an important factor when designing imaging agents in order to reduce problems with background. These stringent conditions are met by the bicyclic structures described in the present invention. Description of the invention Viewed from one aspect the invention provides new peptide-based compounds of Formula I as defined in the claims. These compounds have affinity for integrin receptors, e.g. affinity for the integrin av(33. The compounds of Formula I comprise at least two bridges, wherein one bridge forms a disulphide bond and the second bridge comprises a thioether (sulphide) bond and wherein the bridges fold the peptide moiety into a 'nested' configuration. The compounds of the current invention thus have a maximum of one disulphide bridge per molecule moiety. Compounds defined by the present invention are surprisingly stable in vivo and under the conditions employed during labelling, e.g. during labelling with technetium. These new compounds may be used in therapeutically effective treatments as well as for imaging purposes. The new peptide-based compounds described in the present invention are defined by Formula I: or physiologically acceptable salts thereof wherein G represents glycine, and D represents aspartic acid, and RI represents -(CH2)n- or - (CH2) n-C6H4- , preferably R± represents -(CH2)-, and ri represents a positive integer between 1 and 10, and h represents a positive integer 1 or 2 , and Xi represents an amino acid residue wherein said amino acid possesses a functional side-chain such as an acid or amine preferentially aspartic or glutamic acid, lysine, homolysine, diaminoalcylic acid or diaminopropionic acid, X2 and X4 represent independently an amino acid residue capable of forming a disulphide bond, preferably a cysteine or a homocysteine residue, and X3 represents arginine, N-methylarginine or an arginine mimetic, preferably an arginine, and X5 represents a hydrophobia amino acid or derivatives thereof, preferably a tyrosine, a phenylalanine, a 3-iodo-tyrosine or a naphthylalanine residue, and more preferably a phenylalanine or a 3-iodo-tyrosine residue, and Xg represents a thiol-containing amino acid residue, preferably a cysteine or a homocysteine residue, and X7 is absent or represents a homogeneous biomodifier moiety preferably based on a monodisperse PEG building block comprising 1 to 10 units of said building block, said biomodifier having the function of modifying the pharmacokinetics and blood clearance rates of the said agents. In addition X-/ may cilso represent 1 to 10 amino acid residues preferably glycine, lysine, aspartic acid or serine. In a preferred embodiment of this invention X? represents a biomodifier unit comprised of polymerisation of the monodisperse PEG-like structure, 17-amino-5-oxo-6-aza~ 3,9,12,15-tetraoxaheptadecanoic acid of Formula II, wherein n equals an integer from 1 to 10 and where the C-terminal unit is an amide moiety. Wj is absent or represents a spacer moiety and is preferentially derived from glutaric and/or succinic acid and/or a polyethyleneglycol based unit and/or a unit of Formula II Zi is an antineoplastic agent, a chelating agent or a reporter moiety that can be represented by a chelating agent of Formula IIIwhere .- each R1, R2, R3 and R4 is independently an R group; each R group is independently H or Ci-io alkyl, C3-i0 alkylaryl, C2-io alkoxyalkyl, Ci-io hydroxyalkyl, Ci-io alkylamine, CI-IQ fluoroalkyl, or 2 or more R groups, together with the atoms to which they are attached form a carbocyclic, heterocyclic, saturated or unsaturated ring, or can represent a chelating agent given by formulas a, b, c and d. H0 A preferred example of a chelating agent is represented by formula e. HN NH / N N, HO' OH Conjugates comprising chelating agents of Formula III can be radiolabelled to give good radiochemical purity, RCP, at room temperature, under aqueous conditions at near neutral pH. The risk of opening the disulphide bridges of the peptide component at room temperature is less than at an elevated temperature. A further advantage of radiolabelling the conjugates at room, temperature is a simplified procedure in a hospital pharmacy. The role of the spacer moiety Wx is to distance the relatively bulky chelating agent from the active site of the peptide component. The spacer moiety Wi is also applicable to distance a bulky antineoplastic agent from the active site of the peptide. It is found that the biomodifier, X7, modifies the pharmacokinetics and blood clearance rates of the compounds. The biomodifier effects less uptake of the compounds in tissue i.e. muscle, liver etc. thus giveing a better diagnostic image due to less background interference. The secretion is mainly through the kidneys due to a further advantage of the biomodifier. However the compounds defined in Formula I may also comprise chelating agents, Zl, as defined in Table I. In some aspects of the invention,Zi comprises a reporter moiety where said reporter moiety comprises a radionuclide. Further definisions of chelating agents are listed in the following Table I. Table I: Class of ligand Structure Definitions Amineoxime Y 1-8 can be H, alkyl, aryl or combinations thereof and Y4 or Y5 contains a suitable functionality such that it can be conjugated to the peptide vector - e.g. preferably alkylamine, alkylsulphide, alkoxy, alkyl carboxylate, arylamine, aryl sulphide or a-haloacetyl X= C or N when m'=n'= 1 X> N when m'=n'= 2 CO2H Class of Structure ligand MAG 3 type Definitions P = protecting group (preferably, benzoyl, acetyl, EOE); Yl, Y2 contains a suitable functionality such that it can be conjugated to the peptide vector; preferably H (MAG3), or the side chain of any amino acid, in either L or D form. G4 type ligands Yl, Y2, Y3 - contains a suitable functionality such that it can be conjugated to the peptide vector; preferably H, or the side chain of any amino acid, in either L or D form. Class of ligand Structure Definitions Tetra- amine ligands Y1-Y6 can be H, alkyl, aryl or combinations thereof where the Yl-6 groups contain one or more functional moieties such that the chelate can be conjugated to the vector - e.g. preferably alkylamine, alkylsulphide, alkoxy, alkyl carboxylate, arylamine, aryl sulphide or a-haloacetyl Class of 1igand Cylam type ligands Structure Definitions Yl-5 can be H, alkyl, aryl or combinations thereof and where Yl-5 groups contain one or more functional moieties such that the chelate can be conjugated to the vector - e.g. preferably alkylamine, alkylsulphide, alkoxy, alkyl carboxylate, arylamine, aryl sulphide or a-haloacetyl Class of ligand Structure Definitions Diaminedi phenol Yl, Y2 - H, alkyl, aryl and where Yl or Y2 groups contains a functional moiety such that the chelate can be conjugated to the vector - e.g. preferably alkylaraine, alkylsulphide, alkoxy, alkyl carboxylate, arylamine, aryl sulphide or a-haloacetyl W= C, N m'=n' = 1 or 2 N HYNIC O V= linker to vector or vector itself. Class of ligand Structure Definitions Amide t h i o 1 s P P P = protecting group (preferably, benzoyl, acetyl, EOE); Y 1-5 = H, alkyl, aryl; or Y3 is a L or D amino acid side-chain or glycine.and the carboxylate may be used for conjugation to the vector via an amide bond. Alternatively the RI-S groups may contain additional functionality such that the chelate can be conjugated to the vector - e.g. alkylamine, alkylsulphide, alkoxy, alkyl carboxylate, arylamine, aryl sulphide or a-haloacetyl. In some aspects of the invention of Formula I the Zi moiety comprises the binding of a 18F isotope or an isotope of Cu, incorporation into the agent either as a prosthetic group or by substitution or addition reactions. The resulting compound may thus be used in Positron Emission Tomography (PET) Imaging. In one aspect of the present invention of formula I Zi is represented by an antineoplastic agent. In this aspect the compound will target an angiogenic site associated with cancer and bring the antineoplastic agent to the diseased area. The antineoplastic agent may be represented by cyclophosphainide, chloroambucil, busulphan, methotrexate, cytarabine, fluorouracil, vinblastine, paclitaxel, doxorubicin, daunorubicin, etoposide, teniposide, cisplatin, amsacrine, docetaxel, but a, wide range of other antineoplastic agents may also be used. The peptide component of the conjugates described herein have preferably no free amino- or carboxy-termini. This introduces into these compounds a significant increase in resistance against enzymatic degradation and as a result they have an increased in vivo stability as compared to many known free peptides. As used herein the term 'amino acid' refers in its broadest sense to proteogenic L-amino acids, D-amino acids, chemically modified amino acids, N-methyl, Ca-methyl and amino acid side-chain mimetics and unnatural amino acids such as riaphthylalanine. Any naturally occurring amino acid or mimetics of such natural occurring amino acids are preferred. Some preferred embodiments of the compounds of formula I are illustrated by compounds I-IV below: (Figure Remove) In most cases, it: is preferred that the ammo acids in the peptide are all in the L-form. However, in some embodiments of the invention one, two, three or more of the araino acids in the peptide are preferably in the D-form. The inclusion of such D-form amino acids can have a significant effect on the serum stability of the compound. According to the present invention, any of the amino acid residues as defined in formula I may preferably represent a naturally occurring arnino acid and independently in any of the D or I, conformations . Some of the compounds of the invention are high affinity RGD based vectors. As used herein the term 'high affinity RGD based vector' refers to compounds that have a Ki of The present invention also provides a pharmaceutical composition comprising an effective amount (e.g. an amount effective for enhancing image contrast in in vivo imaging) of a compound of general formula I or a salt thereof, together with one or more pharmaceutically acceptable adjuvants, excipients or diluents. The invention further provides a pharmaceutical composition for treatment of a disease comprising an effective amount of a compound of general formula I, or an acid addition salt thereof, together with one or more pharmaceutically acceptable adjuvants, excipients or diluents. Other representative spacer (Wi) elements include structural-type polysaccharides, storage-type polysaccharides, polyamino acids and methyl and ethyl esters thereof, and polypeptides, oligosaccharides and oligonucleoti.des, which may or may not contain enzyme cleavage sites. The reporter moieties (Zj) in the contrast agents of the invention may be any moiety capable of detection either directly or indirectly in an in vivo diagnostic imaging procedure. Preferably the contrast agent comprises one reporter. Preferred are moieties which emit or may be caused to emit detectable radiation (e.g. by radioactive decay). For MR imaging the reporter will either be a non zero nuclear spin isotope (such as 19F) or a material having unpaired electron spins and hence paramagnetic, superparamagnetic, ferrimagnetic or ferromagnetic properties; for light imaging the reporter will be a light scatterer (e.g. a coloured or uncoloured particle), a light absorber or a light emitter; for magnetometric imaging the reporter will have detectable magnetic properties; for electrical impedance imaging the reporter will affect electrical impedance; and for scintigraphy, SPECT, PET, and the like, the reporter will be a radionuclide. Stated generally, the reporter may be (1) a chelatable metal or polyatomic metal-containing ion (i.e. TcO, etc), where the metal is a high atomic number metal (e.g. atomic number greater than 37), a paramagentic species (e.g. a transition metal or lanthanide), or a radioactive isotope, (2) a covalently bound non-metal species which is an unpaired electron site (e.g. an oxygen or carbon in a persistant free radical), a high atomic number non-metal, or a radioisotope, (3) a polyatomic cluster or crystal containing high atomic number atoms, displaying cooperative magnetic behaviour (e.g. superparamagnetisrn, ferrimagnetism or ferromagnetism) or containing radionuclides. Examples of particular preferred reporter groups (Zi) are described in more detail below. Chelated metal reporters are preferably chosen from the group below; 90Y, 99mTc, inlri, 47Sc, 67Ga, 51Cr, 177mSn, 67Cu, 167Tm, 97Ru, !88Re, 177Lu, 199Au, 203Pb and mCe. The metal ions are desirably chelated by chelant groups on the linker moiety. Further examples of suitable chelant groups are disclosed in US-A-4647447, WO89/00557, US-A-5367080, US-A-5364613. Methods for metallating any chelating agents present are within the level of skill in. the art. Metals can be incorporated into a chelant moiety by any one of three general methods: direct incorporation, template synthesis and/or transmetallation. Direct incorporation is preferred. Thus it is desirable that .the metal ion be easily complexed to the chelating agent, for example, by merely exposing or mixing an aqueous solution of the chelating agent-containing moiety with a metal salt in an aqueous solution preferably having a pH in the range of about 4 to about 11. The salt can be any salt, but preferably the salt is a water soluble salt of the metal such as a halogen salt, and more preferably such salts are selected so as not to interfere with the binding of the metal ion with the chelating agent. The chelating agent-containing moiety is preferrably in aqueous solution at a pH of between about 5 and about 9, more preferably between pH about 6 to about 8. The chelating agent-containing moiety can be mixed with buffer salts such as citrate, carbonate, acetate, phosphate and borate to produce the optimum pH. Preferably, the buffer salts are selected so as not to interfere with the subsequent binding of the metal ion to the chelating agent. The following isotopes or isotope pairs can be used for both imaging and therapy without having to change the radiolabeling methodology or chelator: 47Sc2i; 141Ce58; 188Re75; 177LU71; 199AU79; 47Sc21; 131I53; 67Cu29; 131I53 and 123I53; 188Re75 and 99mTc43; 9°Y39 and 87Y39; 47Sc21 and 44Sc21; 9QY39 and 123I53; "6Sm62 and 153Sm62; and 90Y39 and U1ln49. Preferred non-metal atomic reporters include radioisotopes such as 123I, 131I and 18F as well as non zero nuclear spin atoms such as 19F, and heavy atoms such as I. In a further embodiment of this invention, the use of radioisotopes of iodine or fluorine is specifically contemplated. For example, if the peptide or linker is comprised of substituents that can be chemically substituted by iodine or fluorine in a covalent bond forming reaction, such as, for example, substituents containing hydroxyphenyl or p-nitrobenzoyl functionality, such substituents can be labeled by methods well known in the art with a radioisotope of iodine or fluorine respectively. These species can be used in therapeutic and diagnostic imaging applications. While, at the same time, a metal attached to a chelating agent on the same peptide-linker can also be used in either therapeutic or diagnostic imaging applications. A preferred embodiment of the invention relates to a radiolabelled agent of general formula (I), particularly for use in tumour imaging. The diagnostic agents of the invention may be administered to patients for imaging in amounts sufficient to yield the desired contrast with the particular imaging technique. Where the reporter is a metal, generally dosages of from 0.001 to 5.0 mmoles of chelated imaging metal ion per kilogram of patient bodyweight are effective to achieve adequate contrast enhancements. Where the reporter is a radionuclide, dosages of 0.01 to 100 mCi, preferably 0.1 to 50 mCi will normally be sufficient per 70kg bodyweight. The dosage of the compounds of the invention for therapeutic use will depend upon the condition being treated, but in general will be of the order of from 1 pmol/kg to 1 mmol/kg bodyweight. The compounds according to the invention may therefore be formulated for administration using physiologically acceptable carriers or excipients in a manner fully within the skill of the art. For example, the compounds, optionally with the addition of pharmaceutically acceptable excipients, may be suspended or dissolved in an aqueous medium, with the resulting solution or suspension then being sterilized. The compounds of formula I may be therapeutically effective in the treatment of disease states as well as detectable in in vivo imaging. Thus for example the vector on the reporter moieites may have therapeutic efficacy, e.g. by virtue of the radiotherapeutic effect or a raaionuciiae reporter of the vector moiety. Use of the compounds of formula I in the manufacture of therapeutic compositions (medicament) and in methods of therapeutic or prophylactic treatment, preferably treatment of cancer, of the human or animal body are thus considered to represent further aspects of the invention. Further examples of the reporters which may be used in the context of the current application are given on pages 63-66 and 70-86 of W098/47541 and the disclosures made on these pages are incorporated herein by reference in their entirety. It is hereby asserted that each and every reporter or part thereof disclosed on the aforementioned pages is considered to be part of the description of the invention contained in this application. Viewed from a further aspect the invention provides the use of a compound of formula I for the manufacture of a contrast medium for use in a method of diagnosis involving administration of said contrast medium to a human or animal body and generation of an image of at least part of said body. Viewed from a still further aspect the invention provides a method of generating an image of a human or animal body involving administering a contrast agent to said body, e.g. into the vascular system and generating an image of at least a part of said body to which said contrast agent has distributed using scintigraphy, PET or SPECT modalities, wherein as said contrast agent is used an agent of formula I. Viewed from a still further aspect the invention provides a method of generating enhanced images of a human or animal body previously administered with a contrast agent composition comprising a compound as defined by formula I, which method comprises generating an image of at least part of said body. Viewed from a further aspect the invention provides a method of monitoring the effect of treatment of a human or animal body with a drug to combat a condition associated with cancer, preferably angiogenesis, e.g. a cytotoxic agent, said method involving administering to said body an agent of formula I and detecting the uptake of said agent by cell receptors, preferably endothelial cell receptors and in particular avf$3 receptors, said administration and detection optionally but; preferably being effected repeatedly, e.g. before, during arid after treatment with said drug. The compounds of the present; invention can be synthesised using all the known methods of chemical synthesis but particularly useful is the solid-phase methodology of Merrifield employing an automated peptide synthesiser (J. Am. Chem. Soc., 85: 2149 (1964)). The peptides and peptide chelates may be purified using high performance liquid chromatography (HPLC) and characterised by mass spectrometry and analytical HPLC before testing in the in vitro screen. The present invention will now be further illustrated by way of the following non-limiting examples. Examples: Example 1: Lys(cPn216-glutaryl)-Cys-Arg-GlyrAsp-Cys -Phe-Cys]-NHg For details o£ the synthesis of technetium chelate cPn216 the reader is referred to patent, filing GB0116815.2 _l_b) Synthesis of cPn216-glutaric acid intermediate cPn216 (100 mg, 0.29 nunol) was dissolved in DMF (10 mL) arid glutaric anhydride (33 mg, 0.29 mmol) added by portions with stirring. The reaction was stirred for 23 hours to afford complete conversion to the desired product. The pure acid was obtained following RP-HPLC in good yield. 1 c) Synthesis of tetrafluorothiophenyl ester of cPn216-glubaric_acid To cPn216-glutaric acid (300 mg, 0.66 mmol) in DMF (2 mL) was added HATU (249 mg, 0.66 iranol) and NMM (132 (IL, 1.32 mmol). The mixture was stirred for 5 minutes then tetrafluorothiophenol (0.66 nunol, 119 mg) was added. The solution was stirred for 10 minutes then the reaction mixture was diluted with 20 % acetonitrile/water (8 mL) and the product purified by RP-HPLC yielding 110 mg of the desired product following freeze-drying. 1 d) Synthesis of ClCHaCO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys(tBu)-Phe-Cys~NH2 The peptide was synthesised on an ABI 433A automatic peptide synthesiser starting with Rink Amide AM resin on a 0.25 mmol scale using 1 mmol amino acid cartridges. The amino acids were pre-activated using HBTU before coupling. N-terminal amine groups were chloroacetylated using a solution of chloroacetic anhydride in DMF for 30 min. The simultaneous removal of peptide and side-chain protecting groups (except tBu) from the resin was carried out in TFA containing TIS (5 %), H20 (5 %) and phenol (2.5 %) for two hours. After work-up 295 mg of crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 fi CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 run,- product retention time, 6.42 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1118.5, found, at 1118.6). 1 e) Synchesis of thioether cyclo [CHgCO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys_( tBu)zPhe-Cys] -NH2 295 ing of ClCH2CO-Lys-Cys (tBu) -Arg-Gly-Asp-Cys (tBu) -Phe-Cys-NH2 was dissolved in water/acetonitrile. The mixture was adjusted to pH 8 with ammonia solution and stirred for 16 hours. After work-up 217 mg of crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 \\. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 6.18 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1882.5, found, at 1882.6). 1 f) Synthesis of disulphide [Cys2'6] thioether cyclo[CHjCO-Lys-Cys2~Arg-Gly-Asp-Cys6-Phe-Cys] -NH_2_ 217 mg of thioether cyclo [CH2CO~Lys-Cys (tBu) -Arg-Gly-Asp-Cys(tBu)-Phe-Cys]-NH2 was treated with a solution of anisole (500 UL) , DMSO (2 mL) and TFA (100 mL) for 60 min following which the TFA was removed in vacuo and the peptide precipitated by the addition of diethyl ether. Purification by preparative HPLC (Phenomenex Luna 10 |J. CIS (2) 250 x 50 mm column) of the crude material (202 mg) was carried out using 0-30 % B, where A = H2O/0.1 % TFA and B - CH3CN/0.1 % TFA, over 60 min at a flow rate of 50 mL/min. After lyophilisation 112 mg of pure material was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H2O/0.1 % TFA and B - CH3CN/0.1 % TFA; column, Phenomenex Luna 3 p. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 run; product retention time, 5.50 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 968, found, at 971). i. 9) Synthesis of disulfide [Cys2'6] thioether cyclo [CH2CQ-Lys (cPn2l6-glutaryl) -Cys2-Arg;-Gly-Asp-Cys6j-Phe-Cys] -NH2 9.7 mg of disulphide [Cys2"6] thioether cyclo [CH2CO-Lys-Cys-Arg-Gly-Asp-Cys-Phe-Cys]-NH2, 9.1 mg of cPn216 chelate active ester and 6 (1L of N-methylmorpholine was dissolved in DMF (0.5 mL). The mixture was stirred for 3 hours. Purification by preparative HPLC (Phenomenex Luna 5 (I CIS (2) 250 x 21.20 mm column) of the reaction mixture was carried out using 0-30 % B, where A = H2O/0.1 % TFA and B = CH3CN/0.1 % TFA, over 40 min at a flow rate of 10 mL/min. After lyophilisation 5.7 mg of pure material was obtained (Analytical HPLC: Gradient, 0-30 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 (a CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 7.32 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1407.7, found, at 1407.6). Example 2: Synthesis of disulphide [Cys2"6] thioether cyclo [CHjCO-Lys (cPn216-glutaryl) -Cys2-Arg-Gly-Asp-Cys6-Phe-Cys] - (PEG)n-NH2 where n= 1. 2a) Synthesis of 17-(Fmoc-anuno)-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid (Figure Remove) This building block is coupled to the solid-phase using Fmoc chemistry. The coupled form of this building block will be referred to in short as (PEG),, where n is a positive integer. 1' 11-Diazido- 3_i_6i 9 - tr ioxaundecane A solution of dry tetraethylene glycol (19.4 g, 0.100 mol) and methanesulphonyl chloride (25.2 g, 0.220 mol) in dry THF (100 ml) was kept under argon and cooled to 0 °C in an ice/water bath. To the flask was added a solution of triethylamine (22.6 g, 0.220 mol) in dry THF (25 ml) dropwise over 45 min. After 1 hr the cooling bath was removed and stirring was continued for 4 hrs. Water (60 ml) was added. To the mixture was added sodium hydrogencarbonate (6 g, to pH 8) and sodium azide (14.3 g, 0,220 mmol), in that order. THF was removed by distillation and the aqueous solution was refluxed for 24 h (two layers formed). The mixture was cooled and ether (100 ml) was added. The aqueous phase was saturated with sodium chloride. The phases were separated and the aqueous phase was extracted with ether (4 x 50 ml). Combined organic phases were washed with brine (2 x 50 ml) and dried (MgSO4) . Filtration and concentration gave 22.1 g (91%) of yellow oil. The product was used in the next step without further purification. -3 , 6, 9 - tripxauridecanainine To a mechanically, vigorously stirred suspension of 1,11-diazido-3, 6, 9-trioxaundecane (20.8 g, 0.085 mol) in 5% hydrochloric acid (200 ml) was added a solution of triphenylphosphine (19.9 g, 0.073 mol) in ether (150 ml) over 3 hrs at room temperature. The reaction mixture was stirred for additional 24 hrs. The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 40 ml) . The aqueous phase was cooled in an ice/water bath and pH was adjusted to ca 12 by addition of KOH. The product was extracted into dichloromethane (5 x 50 ml) . Combined organic phases were dried (MgS04) . Filtration and evaporation gave 14.0 g (88%) of yellow oil. Analysis by MALDI-TOF mass spectroscopy (matrix: a-cyano-4-hydroxycinnamic acid) gave a M+H peak at 219 as expected. Further characterisation using 3H (500 MHz) and 13C (125 MHz) NMR spectroscopy verified the structure . 1 T^Azi do- 5-oxo- 6-aza-3 , 9, 12, 15-tetraoxaheptadecanoic acid To a solution of ll-azido-3 , 6 , 9 -trioxaundecanamine (10.9 g, 50.0 mmol) in dichloromethane (100 ml) was added diglycolic anhydride (6.38 g, 55.0 mmol) . The reaction mixture was stirred overnight. HPLC analysis (column Vydac 218TP54; solvents: A - water/0.1% TFA and B = acetonitrile/0 . 1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm) , showed complete conversion of starting material to a product with retention time 18.3 min. The solution was concentrated to give quantitative yield of a yellow syrup. The product was analysed by LC-MS (ES ionisation) giving [MH] + at 335 as expected, XH (500 MHz) and 13C (125 MHz) NMR spectroscopy was in agreement with structure The product was used in the next step without further purification. 17_-.Arninp-5-oxo-6-aza-3 , 9 ,12, 15-tetraoxaheptadecanoic acid A solution of 17-azido-5-oxo-6-aza-3,9,12, 15-tetraoxaheptadecanoic acid (8.36 g, 25.0 mmol) in water (100 ml) was reduced using H2(g)-Pd/C (10%). The reaction was run until LC-MS analysis showed complete conversion of starting material (column Vydac 218TP54; solvents: A = water/0.1% TFA and B = acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm, ES ionisation giving M+H at 335 for starting material and 309 for the product). The solution was filtered and used directly in the next step. 17- (Fmoc-amino)-5-o_xo-6-aza-3 , 9 , 12 , 15-tetraoxaheptadecanoic ac id To the aqueous solution of 17-amino-5-oxo-6-aza-3,9,12,15-tetraoxaheptadecanoic acid from above(corresponding to 25.0 mmol amirto acid) was added sodium bicarbonate (5.04 g, 60.0 mmol) and dioxan (40 ml). A solution of Fmoc-chloride (7.11 g, 0.275 mol) in dioxan (40 ml) was added dropwise. The reaction mixture was stirred overnight. Dioxan was evaporated off (rotavapor) and the aqueous phase was extracted with ethyl acetate. The aqueous phase was acidified by addition of hydrochloric acid and precipitated material was extracted into chloroform. The organic phase was dried (MgS04) , filtered and concentrated to give 11.3 g (85%) of a yellow syrup. The structure was confirmed by LC-MS analysis (column Vydac 218TP54; solvents: A = water/0.1% TFA and B = acetonitrile/0.1% TFA; gradient 40-60% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 254 nm, ES ionisation giving M+H at 531 as expected for the product peak at 5,8 minutes). The analysis showed very low content of side products and the material was used without further purification. 2_b) Synthesi-s of ClCH^CO-Lys-Cys (tBu) -Arg-Gly-Asp-Cys (tBu) I^f-L^YJLll-EIiG)n-NHj_where n- 1 The PEG unit was coupled manually to Rink Amide AM resin, starting ori a 0.25 mmol scale, mediated by HATU activation. The remaining peptide was assembled on an ABI 433A automatic peptide synthesiser using 1 mmol amino acid cartridges. The amino acids were pre-activated using HBTU before coupling. N-terminal amine groups were chloroacetylated using a solution of chloroacetic anhydride in DMF for 30 min. The simultaneous removal of peptide and side-chain protecting groups (except tBu) from the resin was carried out in TFA containing TIS (5 %), H20 (5 %) and phenol (2.5 %) for two hours. After work-up 322 mg of crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 (0. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 run; product retention time, 6.37 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1409, found, at 1415). 1 s_ of thi^e_ther cyclo [CHgCO-Lys-Cys (tBu) -Arg-Gly- 322 ing of ClCH2CO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys(tBu)-Phe-Cys- (PEG) n-NH-,1 was dissolved in water/acetonitrile. The mixture was adjusted to pH 8 with ammonia solution and stirred for 1.6 hours. After work-up crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 p. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 run; product retention time, 6.22 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1373, found, at 1378). 2 d) Synthesis of disulphide [Cys2"6] thioether cyclo[CH2CO-Lys^Cys^Arg-Gly-Asp-Cys^Ph-Cys] - (PEG) n-NH2 where n~ 1 Thioether cyclo [CH2CO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys(tBu) Phe-Cys]-(PEG)n-NH2 was treated with a solution of anisole (200 (IL) , DMSO (2 mL) and TFA (100 mL) for 60 min following which the TFA was removed in vacuo and the peptide precipitated by the addition of diethyl ether. Purificahion by preparative HPLC (Phenomenex Luna 5 \i CIS (2) 250 x 21.20 mm column) of 70 mg crude material was carried out using 0-30 % B, where A = H2O/0.1 % TFA and B = CH-iCN/0.1 % TFA, over 40 min at a flow rate of 10 mL/min. After lyophilisation 46 mg of pure material was obtained (Analytical HPLC: Gradient, 0-30 % B over 10 min where A = H2O/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 |i CIS (2) 50 x 4.6 mir,; flow, 2 mL/min; detection, UV 214 nm; product retention time, 6.80 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1258.5, found, at 1258.8). 2 e)_ Synthesis of _disulfj.de [Cys^ ] thioether cyclo [CH2CO-Lys_(cPn216-glutaryl) -Cys2-Arg-Gly-Asp-Cys6-Phe-Cys] - (PEG)n-NH2 where n= 1 13 mg of [Cys2"6] cyclo [CH2CO-Lys-Cys-Arg-Gly-Asp-Cys-Phe-Cys]-(PEG)n-NH2, 9.6 mg of cPn216 chelate active ester and 8 |4L of N-methylmorpholine was dissolved in DMF (0.5 mL) . The mixture was stirred for 2 hours and 30 minutes. Purification by preparative HPLC (Phenomenex Luna 5 H CIS (2) 250 x 21.20 mm column) of the reaction mixture was carried out using 0-30 % B, where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA, over 40 min at a flow rate of 10 mL/min. After lyophi.lisat.ion 14.2 mg of pure material was obtained (Analytical HPLC: Gradient, 0-30 % B over 10 min where A = H2O/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 |1 CIS (2) 50 x 4.6 mm; .flow, 2 mL/min; detection, UV 214 run; product retention time, 7.87 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1697.8, found, at 1697.9). Example 3: Syjnthesj.£_of._ d^sjjlJ:i^_JLgys2'6 J thioether cycle? [CHgCO- Lys (cPji2_l6^g 1 ut^y^y^CY_siiArg-Gly-Asp--Cys6-Phe--Cys ] - (PEG)n-NH2 where__n=_ 2. 3__a)_Sy_ntji:_es_is of ClCH^CQ-Lys-Cys (tBu) -Arg-Gly-Asp-Cys (tBu) - Assembly of peptide as for example 2 b), both PEG units coupled manually. After work-up crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H2O/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 u. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 6.40 min). 3_b]_Synthesis of thioether cyclo [CH2CO-Lys-Cys( tBu)-Arg-Gly-Asp-Cys (tBu) -Phe-Cys] - (PEGI n-NH2_where n=2 ClCH2CO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys(tBu)-Phe-Cys-(PEG)n-NH2 where n=2 was dissolved in water/acetonitrile. The mixture was adjusted to pH 8 with ammonia solution and stirred for 16 hours. After work-up 380 mg of crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 p. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 run; product retention time, 6.28 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1663, found, at 1670). 3 c) Synthesis of disulphide [Cys2'6] thioether cyclo [CEbCO--Lys-Cys2-Arg-Giy-Asp-Cyss-Phe-Cys] -(PEG)n-NH2 where n= 2. (Figure Remove) 380 ray of thioether cyclo[CH2CO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys (tBu) -Phe-Cys] - (PEG) ri-NH2 where n=2 was treated with a solution of anisole (500 |J.L) , DMSO (2 mL) and TFA (100 mL) for 60 min following which the TFA was removed in vacuo and the peptide precipitated by the addition of diethyl ether. Purification by preparative HPLC (Phenomenex Luna 10 \i CIS (2) 250 x 50 mm column) of the crude material (345 nag) was carried out using 0-30 % B, where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA, over 60 min at a flow rate of 50 mL/min. After lyophilisation 146 mg of pure material was obtained (Analytical HPLC: Gradient, 0-30 % B over 10 min where A = HaO/O.l % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 (J. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 7.42 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1548.6, found, at 1548.8). 3 d) Synthesis of disulphide [Cys2'6] thioether cyclo[CH2CQ-Lys(cPn216-glutaryl)-Cys2-Arg-Gly-Asp-Cys6-Phe-Cys]-(PEG)n-NH2 where n= 2. 146 mg of [Cys2~6] cyclo[CH2CO-Lys-Cys-Arg-Gly-Asp-Cys-Phe-Cys]-(PEG) 2-NH2, 110 mg of cPn216 chelate active ester and 76 [J.L of N-methylmorpholine was dissolved in DMF (6 mL) . The mixture was stirred for 9 hours. Purification by preparative HPLC (Phenomenex Luna 10 (I CIS (2) 250 x 50 mm column) of the reaction mixture was carried out using 0-30 % B, where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA, over 60 min at a flow rate of 50 mL/min. After lyophilisation 164 mg' of pure material was obtained (Analytical HPLC: Gradient, 0-30 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 (.1 CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 run; product retention time, 8.13 min). Further product characterisation was carried out using mass spectrometry: Expected, M+H at 1988.0, found, at 1988.0). Example 4: Syntheses of disulfide [Cys2"6] thioether cyclo [CH2CO-Lys(cPn216-glutaryl) -Cys2-Arg-Gly-Asp-Cys6-Phe-Cys] - (PEG)n-NH2 where n= 4. 4 a) Synthesis of ClCH2CO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys(tBu)- Phe-Cys- (PEG) n-NH2_where n= 4 assembly of peptide as for example 2 b), all four PEG units coupled manually. After work-up crude peptide was obtained (Analytical HPLC: Gradient.;, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 |4. CIS (2) 50 x 4.6 nun; flow, 2 mL/min; detection, UV 214 nm; product retention time, 6.50 min). 4bj__Syn thesis of thioether cyclo [CH2CO-Lys-Cys (tBu)-Arg-Gly-Asp-Cys (tBu) -Phe-Cys]-(PEG]n-NHj_where n= 4 lH, Molocular Wslghl = 2243.659 ClCH2CO-Lys-Cys(tBu)-Arg-Gly-Asp-Cys(tBu)-Phe-Cys-(PEG)4-NII2 was dissolved in water/acetonitrile. The mixture was adjusted to pH 8 with ammonia solution and stirred for 16 hours. After work-up crude peptide was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B - CH;iCN/0.1 % TFA; column, Phenomenex Luna 3 |i C18 (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 6.37 min). Further product characterisation was carried out using mass spectrometry: Expected, [(M+2HJ/2] at 1122.0, found, at 1122.5). 4 c) Synthesis of disulphide [Cys2"6] thioebher cyclo[CH2CO Lys-Cys2-Arg-Gly-Asp-Cys6-Phe-Cys] - (PEG) n-NHa_where n= 4 Thioether cycle [CH2CO-Lys-Cys (tBu) -Arg-Gly-Asp-Cys (tBu)-Phe-Cys]-(PEG)4-NHz was treated with a solution of anisole (100 HL,) , DMSO (1 mL) and TFA (50 mL) for 60 min following which the TFA was removed in vacuo and the peptide precipitated by the addition of diethyl ether. Purification by preparative HPLC (Phenomenex Luna 5 \i CIS (2) 250 x 21.20 mm column) of the crude material (345 mg) was carried out using 5-50 % B, where A = H2O/0.1 % TFA and B = CH3CN/0.1 % TFA, over 40 min at a flow rate of 10 mL/min. After lyophilisation 12 mg of pure material was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 p. CIS (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 4.87 min). 4_dj_Synthesi_s of disulphide [Cys ] thioether cyclo[CH2CO-Lygj£Pn216-g_lutaryl) -Cys2-Arg-Gly-Asp-Cys6-Phe-Cys] - (PEG)n-NH2 where n= 4. 12 mg of disulphide [Cys2~6] thioether cyclo [CH2CO-Lys-Cys-Arg-Gly-Asp-Cys-Phe-Cys] - (PEG)4-NH2, 5.2 mg of cPn216 chelate active ester and 2 flL of N-methylmorpholine was dissolved in DMF (0.5 mL). The mixture was stirred for 7 hours. Purification by preparative HPLC (Phenomenex Luna 5 [A C18 (2) 250 x 21.20 mm column) of the reaction mixture was carried out using 5-50 % B, where A = H2O/0.1 % TFA and B = CH3CN/0.1 % TFA, over 40 min at a flow rate of 10 mL/min. After lyophilisation 8 mg of pure material was obtained (Analytical HPLC: Gradient, 5-50 % B over 10 min where A = H20/0.1 % TFA and B = CH3CN/0.1 % TFA; column, Phenomenex Luna 3 fl C18 (2) 50 x 4.6 mm; flow, 2 mL/min; detection, UV 214 nm; product retention time, 5.17 min). Further product characterisation was carried out using mass spectrometry: Expected, f(M+2H)/2] at 1284.6, found, at 1284.9). SEQUENCE LISTING Amersham Health AS j Peptide based compound NO 20014954 I N020014954 2001-10-11 1 Patentlii version 3.1 1 8 PRT Artificial sequence Synthetic peptide DISULFID (2)..(5) Disulphide bridge between amino acid residue 2 and 5. THIOETH (1)..(8) Thioether bridge between amino acid residue 1 and 8. 1 Lys Cys Arg Gly Asp Cys Phe Cys WE CLAIM: 1. Peptide based compounds of general formula (I) (Formula Removed) or pharmaceutically acceptable salt thereof wherein G represents glycine D represents aspartic acid Ri represents -(CH2)n- or -(CH2)n-C6H4- wherein n represents a positive integer 1 to 10 h represents a positive integer 1 or 2 Xi represents an amino acid residue wherein said amino acid possesses a functional side-chain such as an acid or amine. X2 and X4 represent independently an amino acid residue capable of forming a disulphide bond, X3 represents arginine, N-methylarginine or an arginine mimetic, Xs represents a hydrophobic amino acid or derivatives thereof, and X6 represents a thiol-containing amino acid residue, and X7 is absent or represents a biomodifier moiety Z1 represents an antineoplastic agent, a chelating agent I or a reporter moiety and Wi is absent or represents a spacer moiety. 2. A compound as claimed in claim 1, wherein any of the amino acid residues are independently in the D or L conformation. 3. A compound as claimed in claim 1, wherein Ri represents -(CH2)-. 4. A compound as claimed in any of claims 1 to 3, wherein Xi represents aspartic acid, glutamic acid, lysine, homolysine or a diaminoalkylic acid or derivatives thereof. 5. A compound as claimed in any of the previous claims, wherein X2, X4 and X6 independently represent a cysteine or homocysteine residue. 6. A compound as claimed in any of the previous claims, wherein X3 represents an arginine residue. 7. Compound as claimed in any of the previous claims, wherein X5 represents a tyrosine, a phenylalanine, a 3-iodo-tyrosine or a naphthylalanine residue. 8. A compound as claimed in any of the previous claims, wherein X7 is absent or comprises 1-10 units of a monodisperse PEG building block. 9. A compound as claimed in any of the previous claims, wherein X7 is absent or comprises 1-10 units of Formula II (Formula Removed) 10. A compound as claimed in any of the previous claims, wherein X7 represent 1-10 amino acid residues. 11. A compound as claimed in any of the previous claims, wherein X7 represent glycine, lysine, aspartic acid or serine residues, preferably glycine. 12. A compound as claimed in any of the previous claims, where Zi is a chelating agent of Formula III (Formula Removed) (III) where: each R1, R2, R3 and R4 is independently an R group; each R group is independently H or Ci-10 alkyl, C3-10 alkylaryl, C2-10 alkoxyalkyl, Ci-10 hydroxyalkyl, Ci-10 alkylamine, Ci-10 fluoroalkyl, or 2 or more R groups, together with the atoms to which they are attached form a carbocyclic, heterocyclic, saturated or unsaturated ring. 13. A compound as claimed in any of the previous claims, where Zi is (Formula Removed) 14. A compound as claimed in any of the previous claims, wherein Zi comprises a reporter moiety. 15. A compound as claimed in claim 14, wherein the reporter moiety comprises metal radionuclides, paramagnetic metal ions, fluorescent metal ions, heavy metal ions or cluster ions. 16. A compound as claimed in claims 14 and 15, wherein the reporter moiety comprises 90Y, 99Tc, l11In, 47Sc, 67Ga, 51Cr, 77mSn, 67Cu, 167Tm, 97Ru, 188Re, 177Lu, 199Au, 203Pb, 141Ce or 18F. 17. A compound as claimed in claims 1-16, wherein the reporter moiety is 99mTc 18. A compound as claimed in claims 1-11, where Zi is an antineoplastic agent. 19. A compound as claimed in claim 18, where Zi represent cyclophosphamide, chloroambucil, busulphan, methotrexate, cytarabine, fluorouracil, vinblastine, paclitaxel, doxorubicin, daunorubicin, etoposide, teniposide, cisplatin, amsacrine or docetaxel. 20. A compound as claimed in any of the previous claims, where Wi is glutaric or succinic acid. 21. A compound as claimed in claim 1, defined by the following formulas Compound I (Formula Removed) 22. A pharmaceutical composition comprising an effective amount of a compound of general Formula (I) or a salt thereof, together with one or more pharmaceutically acceptable adjuvants, excipients or diluents for use in enhancing image contrast in in vivo imaging or for treatment of a disease. 23. A method of generating enhanced images of a human or animal body comprising administering a contrast agent composition comprising a compound as claimed in claim 1, which method comprises generating an image of at least part of said body. 24. A method of monitoring the effect of treatment of a human or animal body with a drug to combat a condition associated with cancer, said method involving administering to said body a compound or composition as claimed in any one of claims 1 to 22 and detecting the uptake of said compound or composition by cell receptors, said administration and detection optionally but preferably being effected repeatedly, e.g. before, during and after treatment with said compound or composition. 25. A method of treating cancer or a related disease in a human or animal body which comprises the administration of an effective amount of a compound or composition as claimed in any one of claims 1 to 22. 26. A compound as claimed in any one of claims 1 to 12 for use in the manufacture of a medicament for the therapeutic or prophylactic treatment of cancer or a related disease. |
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02218-delnp-2003-correspondence-others.pdf
02218-delnp-2003-description (complete)-12-06-2008.pdf
02218-delnp-2003-description (complete).pdf
02218-delnp-2003-pct-notification.pdf
02218-delnp-2003-pct-request form.pdf
02218-delnp-2003-pct-search report.pdf
2218-DELNP-2003-Abstract-(12-06-2008).pdf
2218-DELNP-2003-Claims-(12-06-2008).pdf
2218-DELNP-2003-Correspondence-Others-(11-08-2008).pdf
2218-DELNP-2003-Correspondence-Others-(12-06-2008).pdf
2218-delnp-2003-correspondence-others-(31-12-2007).pdf
2218-DELNP-2003-Form-1-(12-06-2008).pdf
2218-delnp-2003-form-1-(31-12-2007).pdf
2218-DELNP-2003-Form-2-(12-06-2008).pdf
2218-DELNP-2003-Form-3-(11-08-2008).pdf
2218-DELNP-2003-GPA-(12-06-2008).pdf
2218-DELNP-2003-Others-Document-(12-06-2008).pdf
2218-delnp-2003-others-document-(31-12-2007).pdf
2218-DELNP-2003-PA-(11-08-2008).pdf
2218-DELNP-2003-Petition-137-(12-06-2008).pdf
2218-DELNP-2003-Petition-138-(12-06-2008).pdf
Patent Number | 222862 | |||||||||||||||||||||
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Indian Patent Application Number | 02218/DELNP/2003 | |||||||||||||||||||||
PG Journal Number | 37/2008 | |||||||||||||||||||||
Publication Date | 12-Sep-2008 | |||||||||||||||||||||
Grant Date | 26-Aug-2008 | |||||||||||||||||||||
Date of Filing | 18-Dec-2003 | |||||||||||||||||||||
Name of Patentee | GE HEALTHCARE AS | |||||||||||||||||||||
Applicant Address | NYCOVEIEN 1-2,P.O BOX 4220 NYDALEN,N-0401 OSLO,NORWAY | |||||||||||||||||||||
Inventors:
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PCT International Classification Number | C07K 7/00 | |||||||||||||||||||||
PCT International Application Number | PCT/N002/00250 | |||||||||||||||||||||
PCT International Filing date | 2002-07-08 | |||||||||||||||||||||
PCT Conventions:
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