Title of Invention

"A BIS-AMINOETHANETHIOL-TARGETING LIGAND CONJUGATE"

Abstract

The invention provides, in a general sense, bis-aminoethanethiol - targeting ligand conjugate. BAT is conjugated with a variety of ligands for use as an imaging agent for tissue-specific diseases. The drug conjugates of the invention may also be used as a prognostic tool or as a tool to deliver therapeutics to specific sites within a mammalian body. Kits for use in tissue-specific disease imaging are also provided.

Full Text

This application is divisional of the Indian Patent Application No. IN/PCT/2002/01253/DEL Field of the Invention The present invention relates generally to bis-aminoethanethiol - targeting ligand conjugates. The imaging compositions of the invention are useful in delivering a particular drug to the site of the tumor in the form of a EC-drug conjugate and then imaging the site within hours. Description of Related Art Improvement of tumor imaging is extensively determined by development of more tumor specific pharmaceuticals. Due to greater tumor specificity, ligands as well as antibodies have opened a new era in detection of tumors and undergone extensive preclinical development and evaluation. (Mathias et al., 1996, 1997a, 1997b). Although CT and MRI provide considerable anatomic information about the location and the extent of tumors, these imaging modalities cannot adequately differentiate invasive lesions from edema, radiation necrosis, grading or gliosis. PET and SPECT can be used to localize and characterize tumors by measuring metabolic activity. The development of new tumor hypoxia agents is clinically desirable for detecting primary and metastatic lesions as well as predicting time to recurrence. None of the contemporary imaging modalities accurately measures hypoxia since the diagnosis of tumor hypoxia requires pathologic examination. It is often difficult to predict the outcome of a therapy for hypoxic tumor without knowing at least the baseline of hypoxia in each tumor treated. Although the Eppendorf polarographic oxygen microelectrode can measure the oxygen tension in a tumor, this technique is invasive and needs a skillful operator. Additionally, this technique can only be used on accessible tumors (e.g., head and neck, cervical) and multiple readings are needed. Therefore, an accurate and easy method of measuring tumor hypoxia will be useful for patient selection. However, tumor to normal tissue uptake ratios vary depending upon the pharmaceuticals used. Therefore, it would be rational to correlate tumor to normal tissue uptake ratio with the gold standard Eppendorf electrode measures of hypoxia when new pharmaceuticals are introduced to clinical practice. Several compounds have been labeled using nitrogen and sulfur chelates (Blondeau et aL, 1967; Davison et aL, 1980). Bis-aminoethanethiol tetradentate ligands. also called diaminodithol compounds, are known to form very stable complexes on the basis of efficient binding to two thiolsulfiir and two amine nitrogen atoms. EC can be labeled easily and efficiently with high purity and stabiUty, and is excreted through the kidney by active tubular transport (Surma et aL, 1994; Van Nerom et aL, 1990, 1993; Verbruggen etaL. 1990,1992). SUMMARY OF THE INVENTION The present invention overcomes these and other drawbacks of the prior art by providing a new labeling strategy to target tissues for imaging. The invention provides bis-aminoethanethiol - targeting ligand conjugates. The present invention provides compositions for tissue specific disease imaging. The imaging compositions of the invention generally include ethylenedicysteine and a tissue specific ligand conjugated to the ediylenedicysteine on one or both of its acid arms. The terms "EC-tissue specific ligand conjugate," "EC-derivative" and "EC-drug conjugate" are used interchangeably herein to refer to the unlabeled ethylenedicysteine-ttssue specific ligand compound. As used herein, the term "conjugate" refers to a covalently bonded compound. Ethylenedicysteine is a bis-aminoethanethiol (BAT) tetradentate ligand, also known as diaminodithiol (DADT) compounds. Such compounds are known to form very stable complexes on the basis of efficient binding to two thioi-sulphur and two amine-nitrogen atoms. A tissue, specific ligand is a compound that, when introduced into the body of a mammal or patient, will specifically bind to a specific type of tissue. It is envisioned that the compositions of the invention may include virtually any known tissue specific compound. Preferably, the tissue specific ligand used in conjunction with the present invention will be an anticancer agent, DNA topoisomerase inhibitor, antimetabotite, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercaiator, receptor marker, peptide, nucleotide, organ specific ligand, antimicrobial agent, such as an antibiotic or an antifungal, glutamate pentapeptide or an agent that mimics glucose. The agents that mimic glucose may also be refetred to as "sugars." Preferred anticancer agents include methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide, tomudex, podophyllotoxin, mitoxantrone, captothecin, colchicine, endostatin, fludarabin and gemcitabine. Preferred tumor markers include PSA, ER, PR, AFP, CA-125, CA-199, CEA, interferons, BRCAl, Cytoxan, p53, VEGF, integrins.endostatin, HER-2/neu, antisense markers or a monoclonal antibody. It is envisioned that any other known tumor marker or any monoclonal antibody will be effective for use in conjunction with the invention. Preferred folate receptor targeting ligands include folate, methotrexate and tomudex. Preferred tumor apoptotic cell or tumor hypoxia targeting ligands include annexin V, colchicine, nitroimidazole, mitomycin or metronidazole. Preferred antimicrobials include ampiciliin, amoxicillin, penicillin, cephalosporin, clidamycin, gentamycin, kanamycin, neomycin, natamycin, nafcillin, rifampin, tetracyclin, vancomycin, bleomycin, and doxycyclin for gram positive and negative bacteria and amphotericin B, amantadine, nystatin, ketoconazole, polymycin, acyclovir, and ganciclovir for fungi. Preferred agents that mimic glucose, or sugars, include neomycin, kanamycin, gentamycin, paromycin, amikacin, tobramycin, netilmicin, ribostamycin, sisomicin, micromicin, lividomycin, dibekacin, isepamicin, astromicin, aminoglycosides, glucose or glucosamine. In certain embodiments, it will be necessary to include a linker between the ethylenedicysteine and the tissue specific Ligand. A linker is typically used to increase drug solubility in aqueous solutions as well as to minimize alteration in the affinity of drugs. While virtually any linker which will increase the aqueous solubility of the composition is envisioned for use in conjunction with the present invention, the linkers will generally be either a poly-amino acid, a water soluble peptide, or a single amino acid. For example, when the functional group on the tissue specific ligand, or drug, is aliphatic or phenolic-OH, such as for estractiol, topotecan, paclitaxel, or raloxifen etoposide, the linker may be poly-glutamic acid (MW about 750 to about 15,000), poly-aspartic acid (MW about 2,000 to about 15,000), bromo ethylacetate, glutamic add or aspartic acid. When the drug functional group is aliphatic or aromatic-NHj or peptide, such as in doxorubicin, mitomycin C, endostatin, annexin V, LHRH, octreotide, and VIP, the linker may be poly-glutamic acid (MW about 750 to about 15,000), poly-aspartic acid (MW about 2,000 to about 15,(X)0), glutamic acid or aspartic acid. When the drug functional group is caiboxylic acid or peptide, such as in methotrexate or folic acid, the linker may be ethylenediamine, or lysine. Specific embodiments of the present invention include EC-annexin V, EC-colchicine, EC-nitroimidazole, EC-glutamate pentapeptide, EC- metronidazole, EC-folate, EC-methotrexate, EC-tomudex, EC-neomycin, EC-kanamycin, EC-aminoglycosides, (glucosamine, EC-deoxyglucose), EC-gentamycin, and EC-tobramycin. The present invention further provides a method of synthesizing a ethylenedicysteine drug conjugate or derivative for imaging or therapeutic use. The method includes obtaining a tissue specific ligand, admixing the ligand with ethylenedicysteine (EC) to obtain an EC-tissue specific ligand derivative with a reducing agent to obtain a EC-tissue specific ligand derivative. The tissue specific ligand is conjugated to one or both acid arms of the EC either directly or through a linker as described above. The reducing agent is preferably a dithionite ion, a stannous ion or a ferrous ion. The present invention further provides a method for labeling a tissue specific ligand for imaging, therapeutic use or for diagnostic or prognostic use. The labeling method includes the steps of obtaining a tissue specific ligand, admixing the tissue specific ligand with ethylenedicysteine (EC) to obtain an EC-ligand drug conjugate. For purposes of this embodiment, the tissue specific ligand may be any of the ligands described above or discussed herein. The reducing agent may be any known reducing agent, but will preferably be a dithionite ion, a stannous ion or a ferrous ion. In certain preferred embodiments, the site will be an infection, tumor, heart, lung, brain, liver, spleen, pancreas, intestine or any other organ. The tumor or infection may be located anywhere within the manunalian body but will generally be in the breast, ovary, prostate, endometrium, lung, brain, or liver. The site may also be a folate-positive cancer or estrogen-positive cancer. The invention also provides a idt for preparing a pharmaceutical preparation. The kit generally includes a scaled via or bag, or any other kind of appropriate container, containing a predetermined quantity of an ethylenedicysteine-tissue specific ligand conjugate composition and a sufficient amount of reducing agent. In certain cases, the ethylenedicysteine-tissue specific ligand conjugate composition will also include a linker between the ethylenedicysteine and the tissue specific ligand. The tissue specific ligand may be any ligand that specifically binds to any specific tissue type, such as those discussed herein. When a linker is included in the composition, it may be any linker as described herein. The components of the kit may be in any appropriate form, such as in liquid, frozen or dry form. In a preferred embodiment, the kit components are provided in lyophilized form. The kit may also include an antioxidant and/or a scavenger. The antioxidant may be any known antioxidant but is preferably vitamin C. Most commercially available kits contain glucoheptonate as the scavenger. However, glucoheptonate does not completely react with typical kit components, leaving approximately 10-15% left over. This leftover glucoheptonate will go to a tumor and skew imaging results. Therefore, the inventors prefer to use EDTA as the scavenger as it is cheaper and reacts more completely. Another aspect of the invention is a prognostic method for determining the potential usefulness of a candidate compound for treatment of specific tumors. Currently, most tumors are treated with the "usual drug of choice" in chemotherapy without any indication whether the drug is actually effective against that particular tumor until months, and many thousands of dollars, later. The imaging compositions of the invention are useful in delivering a particular drug to the site of the tumor in the form of a EC-drug conjugate and then imaging the site within hours. In that regard, the prognostic method of the invention includes the steps of determining the site of a tumor within a mammalian body, obtaining an imaging composition which includes a labeled EC which is conjugated to a tumor specific cancer chemotherapy drug candidate, administering the composition to the mammalian body and imaging the site to determine the effectiveness of the candidate drug against the tumor. Typically, the imaging step will be performed within about 10 minutes to about 4 hours after injection of the composition into the mammalian body. Preferably, the imaging step will be performed within about 1 hour after injection of the composition into the mammalian body. The cancer chemotherapy drug candidate to be conjugated to EC in the prognostic compositions may be chosen from known cancer chemotherapy drugs. Such drugs appear in Table 2. There are may be chosen from known cancer chemotherapy drugs. Such drugs appear in Table 2. There are many anticancer agents known to be specific for certain types of cancers. However, not every anticancer agent for a speciflc type of cancer is effective in every patient. Therefore, the present invention provides for the first time a method of determining possible effectiveness of a candidate drug before expending a lot of time and money on treatment. Yet another embodiment of the present invention is a reagent for preparing an imaging agent. The reagent of the invention includes a tissue specific ligand, having an affinity for targeted sites in vivo sufficient to produce a detectable image, covalently linked to a binding moiety. The binding moiety is either directly attached to the tissue specific ligand or is attached to the ligand through a linker as described above. The binding moiety is preferably an N2S2 chelate. The tissue specific Ugand will be covalendy linked to one or botfi acid anns of the EC, either directly or through a linker as described above. The tissue specific Ugand may be any of the ligands as described above. STATEMENT OF INVENTION Present invention relates to a a bis-aminoethanethiol - targeting ligand conjugate, wherein the targeting ligand is, a tumor marker, an antimicrobial, an agent that mimics glucose, or an anticancer agent selected from doxorubicin, tamoxifen, paclitaxel, topotecan, Ihrh, mitomycin c, etoposide, podophyUotoxin, mitoxantrone, camptothecin, endostatin, fludarabin, gemcitabine and tomudex. BRIEF DESCRIPTION OF THE DRAWINGS The foUowing drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. FIG. 1. Synthetic scheme of EC-folate. FIG. 2. Synthetic scheme of EC-MTX (methotrexate). FIG. 3. Synthetic scheme of EC-TDX (tomudex). FIG. 4. Blocking studies for tumor/muscle and tumor/blood count ratios with EC-folate. FIG. 5. Synthetic scheme of EC-MN (metronidazole) FIG. 6A and FIG. 6B. For EC-NIM, FIG. 6A shows the synthetic scheme and FIG. 6B illustrates the 1H-NMR confirmation of the structure. FIG. 7. Synthetic scheme of EC-GAP (pentaglutamate). FIG. 8. Synthetic scheme of EC-COL (colchicine). FIG. 9. Synthetic scheme of EC-neomycin. FIG. lOA. UV wavelength scan of EC. FIG. 1OB. UV wavelength scam of neomycin. FIG. 1OC. UV wavelength scan of EC-neomycin. FIG. 11. Synthetic scheme of EC-Glucosamine FIG. 12. Hexokinase assay of glucose. FIG. 13. Hexokinase assay of glucosamine. FIG. 14. Hexokinase assay of EC-glucosamine. FIG. 15. Hexokinase assay of EC-GAP-glucosamine. FIG. 16. Synthetic scheme of EC-GAP-glucosamine. FIG. 17. Synthetic scheme of EC-deoxyglucose. FIG. 18. Mass spectrometry of EC-deoxyglucose. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Bis-aminoethanethiol tetradentate ligands, also called diaminodithiol compounds, are known to form very stable complexes on the basis of efficient binding to two thiolsulfur and two amine nitrogen atoms. (Davison et al., 1980;1981; Verbruggen et al, 1992). EC, a new renal imaging agent, can be easily and efficiently with high purity and stability is excreted through kidney by active tubular transport. (Verbruggen et al., 1992; Van Nerom et al., 1993; Surma et al., 1994; Verbruggen et al., 1990;Van Nerom et al., 1990; Jamar et al., 1993). Other applications of EC would be chelated for PET and gadolinium, iron or manganese for magnetic resonance imaging (MRI). The present invention utilizes EC to target ligands to specific tissue types for imaging. The advantage of conjugating the EC with tissue targeting ligands is that the specific binding properties of the tissue targeting ligand concentrates the signal over the area of interest. While it is envisioned that the use of EC as a labeling strategy can be effective with virtually any type of compound, some suggested preferred ligands are provided herein for illustration purposes. It is contemplated that the conjugates of the invention may be useful to image not only tumors, but also other tissue-specific conditions, such as infection, hypoxic tissue (stroke), myocardial infarction, apoptotic cells, Alzheimer's disease and endometriosis. The preferred reducing agent for use in the present invention is stannous ion in the form of stannous chloride (SnCl2). However, it is contemplated that other reducing agents, such as dithionate ion or ferrous ion may be usefiil in conjunction with the present invention. It is also contemplated that the reducing agent may be a solid phase reducing agent. The amount of reducing agent can be important as it is necessary to avoid the formation of a colloid. It is often also important to include an antioxidant in the composition to prevent oxidation of the ethylenedicysteine. The preferred antioxidant for use in conjunction with the present invention is vitamin C (ascorbic acid). However, it is contemplated that other antioxidants, such as tocopherol, pyridoxine, thisunine or rutin, may also be useful. In general, the ligands for use in conjunction with the present invention will possess either amino or hydroxy groups that are able to conjugate to EC on either one or both acid arms. If amino or hydroxy groups are not available (e.g., acid functional group), a desired ligand may still be conjugated to EC using the methods of the invention by adding a linker, such as ethylenediamine, amino propanol, diethylenetriamine, aspartic acid, polyaspartic acid, glutamic acid, polyglutamic acid, or lysine. Ligands contemplated for use in the present invention include, but are not limited to, angiogenesis/antiangiogenesis ligands, DNA topoisomerase inhibitors, glycolysis markers, antimetabolite ligands. apoptosis/hypoxia ligands, DNA intercalators, receptor markers, peptides, nucleotides, antimicrobials such as antibiotics or antifungals, organ specific ligands and sugars or agents that mimic glucose. EC itself is water soluble. It is necessary that the EC-drug conjugate of the invention also be water soluble. Many of the ligands used in conjunction with the present invention will be water soluble, or will form a water soluble compound when conjugated to EC. If the tissue specific ligand is not water soluble, however, a linker which will increase the solubility of the Ugand may be used. Linkers may attach to an aliphatic or aromatic alcohol, amine or peptide or to a carboxylic and or peptide. Linkers may be either poly amino acid (peptide) or amino acid such as glutamic acid, aspartic acid or lysine. Table 1 illustrates desired linkers for specific drug functional groups. (Table Removed) Examples: A. estradiol, topotecan, paclitaxel, raloxlfen etoposide B. doxorubicin, mitomycin C, endostatin, annexin V. LHRH, octreotide, VIP C. methotrexate, folic acid Complexes and means for preparing such complexes are conveniently provided in a kit form including a sealed vial containing a predetermined quantity of an EC-tissue specific ligand conjugate of the invention to be labeled and a sufficient amount of reducing agent. The kit may also contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutically acceptable salts to adjust the osmotic pressure, buffers, preservatives, antioxidants, and the like. The components of the kit may be in liquid, frozen or dry form. In a preferred embodiment, kit components are provided in lyophilized form. Any of the conunon carriers known to those with skill in the art. such as sterile saline solution or plasma, can be utilized for preparing the injectable solution to diagnostically image various organs, tumors and the like in accordance with this invention. The solution to be injected at unit dosage is from about 0.01 mL to about 10 mL. The labeling strategy of the invention may also be used for prognostic purposes. It is envisioned that EC may be conjugated to known drugs of choice for cancer chemotherapy, such as those listed in Table 2. These EC-drug conjugates may then be labeled and administered to a patent having a tamor. The labeled EC-drug conjugates will specifically bind to the tumor. Imaging may be performed to determine the effectiveness of the cancer chemotherapy drug against that particular patient's particular tumor. In this way, physicians can quickly determine which mode of treatment to pursue, which chemotherapy drug will be most effective. This represents a dramatic improvement over current methods which include choosing a drug and administering a round of chemotherapy. This involves months of the patient's time and many thousands of dollars before the effectiveness of the drug can be determined. The labeled EC-tissue specific ligand conjugates and complexes provided by the invention may be administered intravenously in any conventional medium for intravenous injection such as an aqueous saline medium, or in blood plasma medium. Such medium may also contain conventional pharmaceutical adjunct materials such as, for example, pharmaceutically acceptable salts to adjust the osmostic pressure, buffers, preservatives, antioxidants and the like. Among the preferred media are normal saline and plasma. Specific, preferred targeting strategies are discussed in more detail below. Tumor Folate Receptor Targeting The ligands, such as pentetreotide and vasoactive intestinal peptide, bind to cell receptors, some of which are overexpressed on tumor cells (Britton and Granowska, 1996; Krenning et al, 1995; Reubi et al, 1992; Goldsmith et al., 1995; Virgolini et al, 1994). Since these ligands are not immunogenic and are cleared quickly from the plasma, receptor imaging would seem to be more promising compared to antibody imaging. Folic acid as well as antifolates such as methotrexate enter into cells via high affinity folate receptors (glycosylphosphatidylinositol-linked membrane folate-binding protein) in addition to classical reduced-folate carrier system (Westerhof et al, 1991; Orr et al, 1995; Hsueh and Dolnick, 1993). Folate receptors (FRs) are overexposed on many neoplastic ceil types {e.g., lung, breast, ovarian, cervical, colorectal, nasopharyngeal, renal adenocarcinomas, malign melanoma and ependymomas), but primarily expressed only several normal differentiated tissues (e.g., choroid plexus, placenta, thyroid and kidney) (Orr et al, 1995; Weitman et al, 1992a; Campbell et al, 1991; Weitman et al, 1992b; Holm et al, 1994; Ross et al, 1994; Franklin et al, 1994; Weitman et al, 1994). FRs have been used to deliver folate-conjugated protein toxins, drug/antisense oligonucleotides and liposomes into tumor cells overexpressing the folate receptors (Ginobbi et al, 1997; Leamon and Low, 1991; Leamon and Low, 1992; Leamon et al., 1993; Lee and Low, 1994). Furthennore, bispecific antibodies that contain anti-FR entibodies linked to anti-T cell receptor antibodies have been used to target T cells to FR-positive tumor cells and are currently in clinical trials for ovarian carcinomas (Canevari et al., 1993; Bolhuis et al., 1992; Patrick et al., 1997; Coney et al, 1994; Kranz et al., 1995). Similarly, this property has been inspired to develop folate-conjugates for imaging of folate receptor positive tumors (Mathias et al., 1996; Wang et al, 1997; Wang et al, 1996; Mathias et al., 1997b). Results of limited in vitro and in vivo studies with these agents suggest that folate receptors could be a potential target for tumor imaging. In this invention, the inventors developed a series of new folate receptor ligands. These ligands are EC-folate, EC-methotrexate (EC-MTX), EC-tomudex (EC-TDX). Tumor Hypoxia Targeting Tumor cells arc more sensitive to conventional radiation in the presence of oxygen them in its absence; even a small percentage of hypoxic cells within a tumor could limit the response to radiation (Hall, 1988; Bush etal, 1978; Gray etal, 1953). The occurrence of hypoxia in human tumors, in most cases, has been inferred from histology findings and from animal tumor studies. In vivo demonstration of hypoxia requires tissue measurements with oxygen electrodes and the invasiveness of these techniques has limited their clinical application. Misonidazole (MISO) is a hypoxic cell sensitizer, and labeling MISO may be useful for differentiating a hypoxic but metabolically active tumor from a well-oxygenated active tumor by PET or planar scintigraphy. Peptide Imaging of Cancer Peptides and amino acids have been successfully used in imaging of various types of tumors (Wester et a/., 1999; Coenen and Stocklin. 1988; Raderer et ai, 1996; Lambert et al, 1990; Bakker et al, 1990; Stella and Mathew, 1990; Butterfield et al, 1998; Piper et al, 1983; Mochizuki et al, Dickinson and Hiltner, 1981). Glutamic acid based peptide has been used as a drug carrier for cancer treatment (Stella and Mathew, 1990; Butterfield et al, 1998; Piper et al, 1983; Mochizuki et al, 1985; Dickinson and Hiltner, 1981). It is known that glutamate moiety of folate degraded and formed polyglutamate in vivo. ITic poiygiutamate is then re- conjugated to folate to form folyl polyglutamate, which is involved in glucose metaboiisnL Labeling glutamic acid peptide may be useful in differentiating the malignancy of the tumors. In this invention, the inventors report the synthesis of EC-glutamic acid pentapeptide imd evaluate its potential use in imaging tumors. Imaging Tumor Apoptotic Cells Apoptosis occurs during the treatment of cancer with chemotherapy and radiation (Lennon et al, 1991; Abrams et al, 1990; Blakcnberg et al, 1998; Blakenberg et al, 1999; Tail and Smith, 1991) Annexin V is known to bind to phosphotidylserin, which is overexpressed by tumor apoptotic cells (Blakenberg et al., 1999; Tait and Smith, 1991). Assessment of apoptosis by annexin V would be usefiil to evaluate the efficacy of therapy such as disease progression or regression. In this invention, the inventors synthesize EC-anncxin V (EC- ANNEX) and evaluate its potential use in imaging tumors. Imaging Tumor Angiogenesis Angiogenesis is in part responsible for tumor growth and the development of metastasis. Antimitotic compounds are antiangiogenic and are known for their potential use as anticancer drugs. These compounds inhibit cell division during the mitotic phase of the cell cycle. During the biochemical process of cellular functions, such as cell division, cell motility, secretion, ciliary and flagellar movement, intracellular transport and the maintenance of cell shape, microtubules are involved. It is known that antimitotic compounds bind with high affinity to microtubule proteins (tubulin), disrupting microtubule assembly and causing mitotic arrest of the proliferating cells. Thus, antimitotic compounds arc considered as microtubule inhibitors or as spindle poisons (Lu, 1995). Many classes of antinutotic compounds control microtubule assembly-disassembly by binding to tubulin (Lu, 1995; Goh etal, 1998; Wang et al, 1998; Rowinsky et al., 1990; Imbert, 1998). Compounds such as colchicinoids interact with tubulin on the colchicine-binding sites and inhibit microtubule assembly (Lu,1995; Goh etal, 1998; Wang et al., 1998). Among colchicinoids, colchicine is an effective anti- inflammatory drug used to treat prophylaxis of acute gout. Colchicine also is used in chronic myelocytic leukemia. Although colchicinoids are potent against certain types of tumor growth, the clinical therapeutic potential is limited due to inability to separate the therapeutic and toxic effects (Lu, 1995). However, colchicine may be useful as a biochemical tool to assess cellular functions. In this invention, the inventors developed EC-colchicine (EC-COL) for the assessment of biochemical process on tubulin functions. Imaging Tumor Apoptotic Cells Apoptosis occurs during the treatment of cancer with chemotherapy and radiation. Annexin V is known to bind to phosphotidylserin, which is overexpressed by tumor apoptotic cells. Assessment of apoptosis by annexin V would be useful to evaluate the efficacy of therapy such as disease progression or regression. Thus, EC-annexin V (EC-ANNEX) was developed. Imaging Tumor Hypoxia The assessment of tumor hypoxia by an imaging modality prior to radiation therapy would provide rational means of selecting patients for treatment with bioreductive drugs (e.g., tirapazamine, mitomycin C). Such selection of patients would permit more accurate treatment patients with hypoxic tumors. In addition, tumor suppressor gene (P53) is associated with multiple drug resistance. To correlate the imaging findings with the overexpression of P53 by histopathology before and after chemotherapy would be usefiil in following-up tumor treatment response. EC-2-nitroimidazole and EC-metronidazole were developed. Imaging Tumor Angiogenesis Angiogenesis is in part responsible for tumor growth and the development of metastasis. Antimitotic compounds arc antiangiogenic and are known for their potential use as anticancer drugs. These compounds inhibit cell division during the mitotic phase of the cell cycle. During the biochemical process of cellular functions, such as cell division, cell motility, secretion, ciliary and flagellar movement, intracellular transport and the maintenance of cell shape, microtubules are involved. It is known that antimitotic compounds bind with high affmity to microtubule proteins (tubulin), disrupting microtubule assembly and causing mitotic arrest of the proliferating cells. Thus, antimitotic compounds are considered as microtubule inhibitors or as spindle poisons. Colchicine, a potent antiangiogenic agent, is known to inhibit microtubule polymerization and cell arrest at metapheise. Colchicine (COL) may be useful as a biochemical tool to assess cellular functions. EC-COL was then developed. Imaging Hypoxia Due to Stroke Although tumor cells are more or less hypoxic, it requires an oxygen probe to measure the tensions. In order to mimic hypoxic conditions, the inventors imaged 11 patients who had experienced stroke using conjugates that include EC-metronidazole (EC-MN). Metronidazole is a tumor hypoxia marker. Tissue in the area of a stroke becomes hypoxic due to lack of oxygen. All of these imaging studies positively localized the lesions. CT does not show the lesions very well or accurately. MRI and CT in some cases exaggerate the lesion size. The following are selected cases from three patients. Tumor Glycolysis Targeting The ligands, such as polysaccharide (neomycin, kanamycin, tobramycin) and monosaccharide (glucosamine) bind to cell glucose transporter, followed by phosphorylation which are overexpressed on tumor cells(Rogers et al, 1968; FanciuUi et al, 1994; Popovici et al., 1971; Jones et al, 1973; Hermann et al, 2000). Polysaccharide (neomycin, kanamycin, tobramycin) and monosaccharide (glucosamine) induced glucose level could be suppressed by insulin (Harada et al., 1995; MoUer et al., 1991; Offield et al., 1996; Shankar et al., 1998; Yoshino et al., 1999; Villevalois-Cam et al., 2000) Since these ligands are not immunogenic and are cleared quickly from the plasma, metabolic imaging would seem to be more promising compared to antibody imaging. The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. EXAMPLE 1: TUMOR FOLATE RECEPTOR TARGETING Synthesis of EC EC was prepared in a two-step synthesis according to the previously described methods (Ratner and Clarke, 1937; Blondeau et al., 1967; each incorporated herein by reference). The precursor, L-thiazolidine-4-carboxyIic acid, was synthesized (m.p. 195°, reported 196-197°). EC was then prepared (m.p. 237°, reported 251-253°). The structure was confirmed by 'H-NMR and fast-atom bombardment mass spectroscopy (FAB-MS). Synthesis of aminoethylamido analogue of methotrexate (MTX- NHi) MIX (227 ma, 0.5 nunol) was dissolved in 1 ml of HCI solution (2N). The pH value was Synthesis of aminoethylamido analogue of folate (Folate- NH2) Folic acid dihydrate (1 g, 2.0 mmol) was added in 10 ml of water. The pH value was adjusted to 2 using HCI (2 N). To this stirred solution, N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ, 1 g in 10 ml methanol, 4.0 nunol) and ethylenediamine (EDA, 1.3 ml, 18 mmol) were added slowly. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo. The product was precipitated in methanol (50 ml) and further washed with acetone (100 ml) to remove the unreacted EEDQ and EDIT. The product was then freeze-dried and used without further purification. Ninhydrin (2% in methanol) spray indicated the positivity of amino group. The product weighed 0.6 g (yield 60% ) as a yellow powder, m.p. of product: 250° (dec). 'H-NMR (D2O) δ 1.97-2.27 (m, 2H, -CH2 glutamatc of folate), 3.05-3.40 (d, 6H, -CH2CONH(CH2)2NH2), 4.27-4.84 (m, 3H, -CHz-pteridinyl, NH-CH-COOH glutamatc), 6.68-6.70 (d, 2H, aromatic-CO). 7.60-7.62 (d, 2H, aromatic-N), 8.44 (s, IH, ptcridinyl). FAB MS m/z calcd for C21H25N9O5(M)+ 483, found 483.21. Synthesis of ethylenedicystdne- folate (EC- Folate) To dissolve EC, NaOH (2N, 0,1 ml) was added to a stirred solution of EC (114 ma, 0.425 mmol) in water (1.5 ml). To this colorless solution, sulfo-NHS (92.3 mg, 0.425 mmol) and EDC (81.5 mg, 0.425 mmol) were added. Folate-NH2 (205 mg, 0.425 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hours using Spectra/POR molecular porous membrane with molecule cut-off at 500 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was freeze dried. The product weighed 116 mg (yield 35%). m.p. 195° (dec); 'H-NMR (D2O) 61.98-2.28 (m, 2H, -CH2 glutamatc of folate), 2.60-2.95 (m, 4H and -CH2-SH of EC). 3.24-3.34 (m, lOH, -CH2-CO, ethylenediamine of folate and ethylenediamine of EC), 4.27-4.77 (m, 5H, -CH-pteridinyl, NH-CH-COOH glutamatc of folate and NH-CH-COOH of EC). 6.60-6.62 (d, 2H, aromatic-CO), 7.58-7.59 (d, 2H. aromatic-N), 8.59 (s, IH, pteridinyl). Anal, calcd for C29H37N11S20g Na2(8H20). FAB MS m/z (M)+ 777.3 (free of water). C, 37.79; H. 5.75; N, 16.72; S, 6.95. Found: m/z (M)* 777.7 (20), 489.4 (100). C, 37.40; H, 5.42; N. 15.43; S, 7.58. Synthesis of EC-folate is shown in FIG. 1. TABLE 2 DRUGS OF CHOICE FOR CANCER CHEMOTHERAPY The tables that follow list drugs used for treatment of cancer in the USA and Canada and their major adverse effects. The Drugs of Choice listing based on the opinions of Medical Letter consultants. Some drugs are listed for indications for which they have not been approved by the US Food and Drug Administration. Anticancer drugs and their adverse effects follow. For purposes of the present invention, these lists are meant to be exemplary and not exhaustive. DRUGS OF CHOICE (Table Removed) t Available in the USA only for investigational use. t Dose-limiting effects are in bold type. Cutaneous reactions (sometimes severe), hyperpigmentation, and ocular toxicity have been reported with virtually all nonhormonal anticancer drugs. For adverse interactions with other drugs, see the Medical Letter Handbook of Adverse Drug Interactions, 1995. 1. Available in the USA only for investigational use. 2. Megestrol and other hormonal agents may be effective in some pateients when tamoxifen fails. 3. After high-dose chemotherapy (Medical Letter, 34:78, 1992). 4. For rectal cancer, postoperative adjuvant treatment with fluoroutacil plus radiation, preceded and followed by treatment with fluoroutacil alone. 5. Drugs have major activity only when combined with surgical resection. 6. The vitamin A analog isotretinoin (Accutane) can control pre-neoplastic isions (leukoplaka) and decreases the rats of second primary tumors (SE Senner et al., J Natl Cancer Inst. 88:140, 1994). 7. High-risk patients (e.g., high counts, cytogenetic abnormalities, adults) may require additional drugs for Induction, maintenance and "Intensification" (use of additional drugs after achievement of remission). Additional drugs include cyclophosphamide, mitoxantrone and thioguamine. The results of one large controlled trial in the United Kingdom suggest that intensilibation may improve survival in all children with ALL (jm Chassella et al.. Lancet, 348: 143, Jan 21. 1998). 8. Patients with a poor prognosis initially or those who relapse after remission 9. Some patients with acute promyclocytic leukemia have had complete responses to tretinoin. Such treatment can cuase a toxic syndrome characterized primarily by fever and respiratory distress (RP Warrell, Jr et al. N Eng J. Med, 329:177, 1993). 10. Allogenaic HLA Identical sibling bone marrow transplantation can cure 40% to 70% of patients with CML in chroni phase, 15% to 25% of patients with accelerated phase CML, and 50 years, duration of disease > 3 years from diagnosis, and use of one antigen mismatched or matched-unrelated donor marrow. Inteferon alfa may be curative in patients with chronic phase CML who achieve a complete cytogenetic resonse (about 10%); It is the treatment of choices for patients > 50 years old with newly diagnosed chronic phase CML and for all patients who are not candidates for an allogenic bone marrow transplant. Chemotherapy alone is palliative. Synthesis of EC-MTX and EC-TDX Use the same method described for the synthesis of EC-folate, EC-MTX and EC-TDX were prepared. The labeling procedure is the same as described for the preparation of EC-folate except EC-MTX and EC-TDX were used. Synthesis of EC-MTX and EC-TDX is shown in FIG. 2 and FIG. 3. Tissue distribution studies Female Fischer 344 rats (150D25 g) (Harlan Sprague-Dawley, Indianapolis, IN) were inoculated subcutaneously with 0.1 ml of manunary tumor cells from the 13762 tumor cell line suspension (10* cells/rat, a tumor cell line speciHc to Fischer rats) into the hind legs using 25-gauge needles. Studies performed 14 to 17 days after implantation when tumors reached approximately 1 cm diameter. Animals were anesthetized with ketamine (10-15 mg/rat, intraperitoneally) before each procedure. RESULTS Chemistry and Stability of £C-FoIate A simple, fast and high yield aminoethylamido and EC analogues of folate, MTX and TDX were developed. The structures of these analogues were confirmed by NMR and mass spectroscopic analysis. Synthesis of EC-folate was achieved with high (>95%) purity. EXAMPLE 2: TUMOR HYPOXIA TARGETING Synthesis of 2-(2-methyl-5-nitro-'H imidazolyl)ethyIamine (amino analogue of metronidazole, MN- NH2) Amino analogue of mettonidazole was synthesized according to the previously described methods (Hay et al, 1994)' Briefly, metronidazole was converted to a mesylated analogue (m.p. 149-150'C, reported 153-154'C, TLC:ethyl acetate, Rf=0.45), yielded 75%. Mesylated metronidazole was then reacted with sodium azide to afford azido analogue (TLC:ethyl acetate, Rf=0.52), yielded 80%. The azido analogue was reduced by triphenyl phosphine and yielded (60%) the desired amino analogue (m.p. 190-192°C, reported 194-195°C, TLC:ethyl acetate, Rf=0.15). Ninhydrin (2% in methanol) spray indicated the positivity of amino group of MN-NH2- The structure was confirmed by 'H-NMR and mass spectroscopy (FAB-MS) m/z 171(M+H,100). Synthesis of Ethylenedicysteine-Metronidazole (EC- MN) Sodium hydroxide (2N, 0.2 ml) was added to a stirred solution of EC (134 ma, 0.50 mmol) in water (5 ml). To this colorless solution, sulfo-NHS (217 mg, 1.0 mmol) and 1-)C (192 ma. 1.0 mmol) were added. MN-NH: dihydrochloride salt (340 mg, 2.0 mmol) was then added. The mature was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hrs using Spectra/POR molecular porous membrane with cut-off at 500 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product weighed 315 mg (yield 55%). 'H-NMR (D2O) δ 2.93 (s, 6H, nitroimidazole-CHj), 2.60- 2.95 (m, 4H and - CH2-SH of EC), 3.30-3.66 (m, 8H, ethylenediamine of EC and nitromidazole-CH2-CH2-NH2), 3.70-3.99 (t, 2H, NH-CH-CO of EC), 5.05 (t, 4H, metronidazole-CH2-CH2-NH2) (s, 2H, nitroimidazole C=CH). FAB MS m/z 572 (M+, 20). The synthetic scheme of EC-MN is shown in FIG. 5. Synthesis of 3-(2-nitro- 'H-iinidazolyl)propyIamine (amino analogue of nitroimidazole, NIM- NH2) To a stirred mixture containing 2-nitloimidazole (Ig, 8.34 mmol) and Cs2GO3 (2.9g, 8.90 mmol) in dimethyiformaide (DMF, 50 ml), 1,3-ditosylpropane (3.84 g, 9.99 mmol) was added. The reaction was heated at 80°C for 3 hours. The solvent was evaporated under vacuum and the residue was suspended in ethylacetate. The solid was filtered, the solvent was concentrated, loaded on a silica gel-packed column and eluted with hexane:ethylacetate (1:1). The product, 3-tosylpropyl-(2-nitroimidazole), was isolated (1.67g, 57.5%) with m.p. 108-11TC. 'H-NMR (CDCI3) 5 2.23 (m, 2H), 2.48 (S. 3H), 4.06 (t, 2H, J=5.7Hz), 4.52 (t, 2H, J=6.8Hz), 7.09 (S. IH), 7.24 (S. IH), 7.40 (d, 2H, J=8.2Hz).7.77 (d, 2H, J=8.2Hz). Tosylated 2-nitroimidazole (1.33g, 4.08 mmol) was then reacted with sodium azide (Q29 g, 4.49 mmol) in DMF (10 ml) at 100°C for 3 hours. After cooling, water (20 ml) was added and the product was extracted from ethylacetate (3x20 ml). The solvent was dried over MgSO4 and evaporated to dryness to afford azido analogue (0.6 g. 75%, TLC: hexane:ethyl acetate; 1:1, Rf=0.42). 'H-NMR (CDCI3) 5 2.14 (m, 2H), 3.41 (t, 2H, J=6.2Hz), 4.54 (t, 2H, J=6.9Hz), 7.17 (S. 2H). The azido analogue (0.57 g, 2.90 mmol) was reduced by taphenyl phosphine (1.14 g, 4.35 mmol) in tetrahydrofuran (PHI;) at room temperature for 4 hours. Concentrate HCI (12 ml) was added and heated for additional 5 hours. The product was extracted from ethylacetate and water mixture. The ethylacetate was dried over MgSO4 and evaporated to dryness to afford amine hydrochloride analogue (360 ma, 60%). Ninhydrin (2% in methanol) spray indicated the positivity of amino group of NIM- NH. 'H-NMR (D2O) 5 2.29 (m, 2H), 3.13 (t, 2H, J=7.8Hz), 3.60 (br, 2H), 4.35 (t, 2H, J=7.4Hz), 7.50 (d, IH, J=2. lHz),7.63 (d, IH, J=2. IHz). Synthesis of ethylenedicysteine-nitroimidazole (EC- NIM) Sodium hydroxide (2N, 0.6 ml) was added to a stirred solution of EC (134 ma, 0.50 mmol) in water (2ml). To this colorless solution, sulfo-NHS (260.6 mg, 1.2 mmol), EDC (230 ma, 1.2 mmol) and sodium hydroxide (2N, 1 ml) were added. NIM-NH2 hydrochloride salt (206.6 mg, 1.0 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hrs using Spectra/POR molecular porous membrane with cut-off at 500 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product weighed 594.8 mg (yield 98%). The synthetic scheme of EC-NIM is shown in FIG. 6A. The structure is confirmed by 'H-NMR (D2O) (HG. 6B). Tissue distribution studies of EC-MN Female Fischer 344 rats (150D25 g) (Harlan Sprague-Dawley, Indianapolis, IN) were inoculated subcutaneously with 0.1 ml of mammary tumor cells from the 13762 tumor cell line suspension (10* cells/rat, a tumor cell line speciflc to Fischer rats) into the hind legs using 25-gauge needles. Studies performed 14 to 17 days after implantation when tumors reached approximately 1 cm diameter. Rats were anesthetized with ketamine (10-15 mg/rat, intraperitoneally) before each procedure. Polarographic oxygen microelectrode pO2 measurements To confirm tumor hypoxia, intratumoral pO2 measurements were performed using the Eppendorf computerized histographic system. Twenty to twenty-five pO2 measurements along each of two to three linear tracks were performed at 0.4 mm intervals on each tumor (40-75 measurements total). Tumor pO measurements were made on three tumor-bearing rats. Using an on-line computer system, the pot measurements of each track were expressed as absolute values relative to the location of the measuring point along the track, and as the relative frequencies within a pO2 histogram between 0 and 100 mmHg with a class width of 2.5 mm. RESULTS Synthesis and stabUity of EC-MN and EC-NIM Synthesis of EC-MN and EC-NIM were achieved with high (>95%) purity Yield was 100%. In blocking studies, tumor/muscle and tumor/blood count density ratios were significantly decreased (p Polarographic oxygen microelectrode pO2 measurements Intratumoral pO2 measurements of tumors indicated the tumor oxygen tension ranged 4.6±1.4 nmHg as compared to normal muscle of 35±10 mmHg. The data indicate that the tumors are hypoxic. EXAMPLE 3: PEPTIDE IMAGING OF CANCER Synthesis of Ethylenedicysteine-Pentaglutamate (EC- GAP) Sodium hydroxide (IN, 1 ml) was added to a stirred solution of EC (200 mg, 0.75 mmol) in water (10 ml). To this colorless solution, sulfo-NHS (162 mg, 0.75 mmol) and EDC (143 mg, 0.75 mmol) were added. Pentaglutamate sodium salt (M.W. 750-1500, Sigma Chemical Company) (500 mg, 0.67 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hrs using Spectra/POR molecular porous membrane with cut-off at 500 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product in the salt form weighed 0.95 g. The synthetic scheme of EC-GAP is shown in FIG. 7. RESULTS Stability Assay of EC-GAP EC-GAP found to be stable at 0.5, 2 and 4 hrs in dog serum samples. There was no degradation products observed. EXAMPLE 4: IMAGING TUMOR APOPTOTIC CELLS Synthesis of Ethylenedicysteine-Annexin V (EC-ANNEX) Sodium bicarbonate (IN, 1 ml) was added to a stirred solution of EC (5 mg, 0.019 mmol). To this colorless solution, sulfo-NHS (4 mg, 0.019 mmol) and EDC (4 mg, 0.019 mmol) were added. Annexin V (M.W. 33 kD, human, Sigma Chemical Company) (0.3 mg) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hrs using Spectra/POR molecular porous membrane with cut-off at 10,000 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product in the salt form weighed 12 mg. RESULTS Stability Assay of EC-ANNEX EC-ANNEX found to be stable at 0.5, 2 and 4 hrs in dog serum samples. There was no degradation products observed. EXAMPLE 5: IMAGING TUMOR ANGIOGENESIS Synthesis of (Amino Analogue of Colchcine, COL-NH2) Demethylated amino and hydroxy analogue of colchcine was synthesized according to the previously described methods (Orr et al, 1995). Briefly, colchicine (4 g) was dissolved in 100 ml of water containing 25% sulfuric acid. The reaction mixture was heated for 5 hours at 100°C. The mixture was neutralized with sodium carbonate. The product was filtered and dried over freeze dryer, yielded 2.4 g (70%) of the desired amino analogue (m.p. 153-155°C, reported 155-157°C). Ninhydrin (2% in methanol) spray indicated the positivity of amino group of COL-NH2. The structure was confirmed by 'H-NMR and mass spectroscopy (FAB-MS). 'H-NMR (CDC 13)6 8.09 (S, IH), 7.51 (d, IH, J=12 Hz), 7.30 (d, IH, J=12Hz), 6.56 (S, IH), 3.91 (S, 6H), 3.85 (m, IH), 3.67 (S, 3H), 2.25-2.52 (m, 4H). m/z 308.2(M*,20), 307.2 (100). Synthesis of Ethylmedicysteine-Colchdne (EC-COL) Sodium hydroxide (2N, 0.2 ml) was added to a stirred solution of EC (134 mg, 0.50 mmol) in water (5 ml). To this colotiess solution, sulfo-lSfHS (217 mg, 1.0 mmol) and EDC (192 mg, 1.0 mmol) were added. COL-NH2 (340 mg, 2.0 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hrs using Spectra/POR molecular porous membrane with cut-off at 500 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product weighed 315 mg (yield 55%). 'H-NMR (D2O) δ 7.39 (S, IH), 7.20 (d, IH, J=l2Hz), 7.03 (d, IH, J=l2Hz), 6.78 (S,1H), 4.25-4.40 (m, 1H), 3.87 (S, 3H, -OCH3), 3.84 (S, 3H, -OCH3), 3.53 (S, 3H, -OCH3), 3.42-3.52 (m, 2H), 3.05-3.26 (m, 4H), 2.63-2.82 (m, 4H), 2.19-2.25 (m, 4H). FAB MS m/z 580 (sodium salt, 20). The synthetic scheme of EC-COL is shown in FIG. 8. RESULTS Synthesis and stabilty of EC-COL Synthesis of EC-COL was achieved with high (>95%) purity (FIG. 8). EC-COL was found to be stable at 0.5, 2 and 4 hrs in rabbit serum samples. There was no degradation products observed. TUMOR GLYCOLYSIS TARGETING EXAMPLE 6: DEVELOPMENT OF EC-NEOMYCIN Synthesis of EC EC was prepared in a two-step synthesis according to the previously described methods (Ratner and Clarke, 1937; Blondeau et al, 1967). The precursor, L-thiazolidine-4-carboxylic acid, was synthesized (m.p. 195°, reported 196-197°). EC was then prepared (m.p. 237°, reported 251-253°). The structure was confirmed by 'H-NMR and fast-atom bombardment mass spectroscopy (FAB-MS). Synthesis of Ethylenedicysteine-neomycin (EC-neomycin) Sodium hydroxide (2N, 0.2 ml) was added to a stirred solution of EC (134 mg, 0.50 mmol) in water (5 ml). To this colorless solution, sulfo-NHS (217 mg, 1.0 mmol) and EDC (192 mg, 1.0 mmol) were added. Neomycin trisulfate salt (909 mg, 1.0 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hours using Spectra/POR molecular porous membrane with cut-off at 500 (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product weighed 720 mg (yield 83%). The synthetic scheme of EC-neomycin is shown in FIG. 9. The structure is confirmed by 'H-NMR, mass spectrometry and elemental analysis (Galbraith Laboratories, Inc. Knoxville, TN). Elemental analysis C39H75N10S4 O19.15H20 (C,H,N,S), Calc. C:33.77, H:7.58, N:10.11, S:9.23; found C:32.44, H:5.90. N: 10.47, S: 10.58. UV wavelength of EC-neomycin was shifted to 270.5 nm when compared to EC and neomycin (FIGS. lOA-C) EXAMPLE 7: TUMOR METABOLIC IMAGING WITH EC-DEOXYGLUCOSE Synthesis of £C-deoxyglucose (EC-DG) Sodium hydroxide (1N, 1ml) was added to a stirred solution of EC (110 mg, 0.41 mmol) in water (5 ml). To this colorless solution, sulfo-NHS (241.6 mg, 1.12 mmol) and EDC (218.8 mg, 1.15 mmol) were added. D-Glucosamine hydrochloride salt (356.8 mg, 1.65 mmol) was then added. The mixture was stirred at room temperature for 24 hours. The mixture was dialyzed for 48 hours using Spectra/POR molecular porous membrane with cut-off at 5(X) (Spectrum Medical Industries Inc., Houston, TX). After dialysis, the product was frozen dried using lyophilizer (Labconco, Kansas City, MO). The product in the salt form weighed 568.8 mg. The synthetic scheme is shown in FIG. 17. The structure was confirmed by mass spectrometry (FIG. 18) and proton NMR. . Hexokinase assay To determine if EC-DG mimics glucose phosphorylation, a hexokinase assay was conducted. Using a ready made kit (Sigma Chemical Company), EC-DG, glucosamine and glucose (standard) were assayed at UV wavelength 340 nm. Glucose, EC-DG and glucosamine showed positive hexokinase assay. All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. REFERENCES The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. Blakenberg, Katsikis, Tait et al., "In vivo detection and imaging of phosphatidylserine expression during programmed cell death," Proc Natl. Acad. Sci USA, 95:6349-6354, 1998. Blondeau, Berse, Gravel, "Dimerization of an intermediate during the sodium in liquid ammonia reduction of L-thiazolidine-4-carboxylic acid," Can J. Chent, 45:49-52, 1967. 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Weitman, Weinberg, Coney, Zurawski, Jennings, Kamen, "Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis," Cancer Res, 52:6708-6711, 1992b. Westerhof, Jansen, Emmerik, Kathmann, Rijksen, Jackman, Schomagel, "Membrane transport of natural folates and antifolate compounds in murine LI210 leukemia cells: Role of carrier- and receptor- mediated transport systems," Cancer Res, 51:5507-5513, 1991. Yoshino, Takeda, Sugimoto, et al., "Differential effects of troglitazone and D-chiroinositol on glucosamine-induced insulin resistance in vivo in rats," Metabolism. 48(11):1418-23, 1999. WE CLAIM: 1. A bis-aminoethanethiol - targeting ligand conjugate, wherein the targeting ligand is an agent that mimics glucose. 2. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein the bis-aminoethanethiol chelating ligand is ethylenedicysteine. 3. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said targeting ligand is conjugated to said chelating ligand on one or both acid arms of the chelating ligand. 4. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said agent which mimics glucose is deoxyglucose, glucose, glucosamine, neomycin, kanamycin, gentamycin, paromycin, amikacin, tobramycin, netilmicin, ribostamycin, sisomycin, micromicin, lividomycin, dibekacin, isepamicin, astromicin, or an aminoglycoside. 5. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said bis-aminoethanethiol ligand-targeting ligand conjugate is EC-neomycin. 6. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said bis-aminoethanethiol ligand-targeting ligand conjugate is EC-kanamycin. 7. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said bis-aminoethanethiol ligand-targeting ligand conjugate is EC-aminoglycosides. 8. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said bis-aminoethanethiol ligand-targeting ligand conjugate is EC-gentamycin. 9. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said bis-aminoethanethiol ligand-targeting ligand conjugate is EC-tobramycin. 10. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein said bis- aminoethanethiol ligand-targeting ligand conjugate is EC-deoxyglucose. 11. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein the chelating ligand is conjugated to the targeting ligand with a linker. 12. A bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 11, wherein said linker is a water soluble peptide, an amino acid, a polyaminoacid, glutamic acid, poly glutamic acid, aspartic acid, poly aspartic acid, bromoethyl acetate, ethylenediamiine or lysine. 13. A method of preparing a bis-aminoethanethiol - targeting ligand conjugate as claimed in claim 1, wherein the method comprises the steps: a) obtaining a targeting ligand; and b) reacting said ligand with bis-aminoethanethiol chelating ligand to obtain a bis- aminoethanethiol targeting ligand conjugate 14. The method of preparing a bis-aminoethanethiol - targeting ligand conjugate, as claimed in claim 13, wherein the bis-aminoethanethiol chelating ligand is EC. 15. A bis-aminoethanethiol - targeting ligand conjugate as and when used in the manufacture of a pharmaceutical, the bis-aminoethanethiol ligand of the kind of EC, to image a tumor or an infection site of the kind breast cancer, ovarian cancer, prostate cancer, endometrium, heart, lung, brain, liver, folate (+) cancer, ER (+) cancer, spleen, pancreas, or intestine. 16. A kit for preparing a radiopharmaceutical preparation for imaging a tumor or an infection site, wherein said kit comprising a sealed container including a predetermined quantity of a bis-aminoethanethiol chelating ligand-targeting ligand conjugate composition and a sufficient amount of reducing agent. 17. A kit for preparing a radiopharmaceutical preparation as claimed in claim 16, wherein the reducing agent is selected from a group consisting of dithionite ion, stannous ion and ferrous ion. 18. The kit as claimed in claim 16, wherein the bis-aminoethanethiol chelating ligand is EC. 19. The kit as claimed in claim 16, wherein the kit further comprises a linker conjugating the chelating ligand to the targeting ligand. 20. The kit as claimed in claim 16, wherein the targeting ligand is an agent that mimics glucose. 21. A bis-aminoethanethiol - targeting ligand conjugate, substantially as hereinbefore described with reference to the foregoing examples and accompanying drawings. 22. A method of synthesizing a bis-aminoethanethiol - targeting ligand conjugate, substantially as hereinbefore described with reference to the foregoing examples and accompanying drawings. 23. A kit for preparing a radiopharmaceutical preparation, substantially as hereinbefore described with reference to the foregoing examples and accompanying drawings.

Documents:

7268-delnp-2008-abstract.pdf

7268-delnp-2008-Claims-(21-02-2014).pdf

7268-delnp-2008-claims.pdf

7268-delnp-2008-Correspondence Others-(18-09-2013).pdf

7268-delnp-2008-Correspondence Others-(21-02-2014).pdf

7268-DELNP-2008-Correspondence-Others-(19-03-2010).pdf

7268-delnp-2008-Correspondence-Others-(23-09-2013).pdf

7268-delnp-2008-correspondence-others.pdf

7268-delnp-2008-description (complete).pdf

7268-delnp-2008-drawings.pdf

7268-delnp-2008-form-1.pdf

7268-delnp-2008-form-2.pdf

7268-DELNP-2008-Form-26-(19-03-2010).pdf

7268-delnp-2008-Form-3-(18-09-2013).pdf

7268-delnp-2008-form-3.pdf

7268-delnp-2008-form-5.pdf

7268-delnp-2008-pct-101.pdf

7268-delnp-2008-pct-210.pdf

7268-delnp-2008-pct-220.pdf

7268-delnp-2008-pct-401.pdf

7268-delnp-2008-pct-409.pdf

7268-delnp-2008-pct-416.pdf