ETHYLENEDICYSTEINE (EC)-DRUG CONJUGATES, COMPOSITIONS AND METHODS FOR TISSUE SPECIFIC DISEASE IMAGING

Abstract: The invention provides, in a general sense, a new labeling strategy employing <99m>Tc chelated with ethylenedicysteine (EC). EC is conjugated with a variety of ligands and chelated to <99m>Tc 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.

Description: DESCRIPTION ETHYLENEDICYSTEINE (EC)-DRUG CONJUGATES, COMPOSITIONS AND METHODS FOR TISSUE SPECIFIC DISEASE IMAGING BACKGROUND OF THE INVENTION The government does not own rights in the present invention. 1. Field of the Invention The present invention relates generally to the fields of labeling, radioimaging and chemical synthesis. More particularly, it concerns a strategy for radiolabeling target ligands. It further concerns methods of using those radiolabeled ligands in tumor imaging and tissue- specific disease imaging. 2. Description of Related Art Improvement of scintigraphic tumor imaging is extensively determined by development of more tumor specific radiopharmaceuticals. Due to greater tumor specificity, radiolabeled ligands as well as radiolabeled antibodies have opened a new era in scintigraphic detection of tumors and undergone extensive preclinical development and evaluation. (Mathias et al, 1996, 1997a, 1997b). Radionuclide imaging modalities (positron emission tomography, PET; single photon emission computed tomography, SPECT) are diagnostic cross-sectional imaging techniques that map the location and concentration of radionuclide-labeled radiotracers. 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 radioresponsiveness and 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 radiopharmaceuticals 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 radiopharmaceuticals are introduced to clinical practice. 1 S [ FJFMISO has been used to diagnose head and neck tumors, myocardial infarction, inflammation, and brain ischemia (Martin et al. 1992; Yeh et al. 1994; Yeh et al. 1996; Liu et al. 1994). Tumor to normal tissue uptake ratio was used as a baseline to assess tumor hypoxia (Yet et al. 1996). Although tumor hypoxia using [ 18 F]FMISO was clearly demonstrated, introducing new imaging agents into clinical practice depends on some other factors such as easy availability and isotope cost. Although tumor metabolic imaging using [ 18 F]FDG was clearly demonstrated, introducing molecular imaging agents into clinical practice depends on some other factors such as easy availability and isotope cost.. [ F]fluorodeoxyglucose (FDG) has been used to diagnose tumors, myocardial infarction, and neurological disease. In addition, PET radiosynthesis must be rapid because of short half-life of the positron isotopes. 18 F chemistry is also complex. The 18 F chemistry is not reproducible in different molecules. Thus, it would be ideal to develop a chelator which could conjugate to various drugs. The preferred isotope would be "Tc due to low cost ($0.21/mCi vs. $50/mCi for 18 F) and low energy (140 Kev vs. 571 Kev for 18 F). Pm Tc is easily obtained from a 99 Mo generator. Due to favorable physical characteristics as well as extremely low price, 99m Tc has been preferred to label radiopharmaceuticals . Several compounds have been labeled with 99m Tc 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 Tc(V)O complexes on the basis of efficient binding of the oxo technetium group to two thiolsulfur and two amine nitrogen atoms. 99m Tc-L,L-ethylenedicysteine ( 99m Tc-EC) is a recent and successful example of N 2 S 2 chelates. EC can be labeled with 99ra Tc easily and efficiently with high radiochemical purity and stability, and is excreted through the kidney by active tubular transport (Surma et al, 1994; Van Nerom et al, 1990, 1993; Verbruggen et at " ., 1990, 1992). Other applications of EC would be chelated with galium-68 (a positron emitter, tl/2=68 min) for PET and gadolinium, iron or manganese for magnetic resonance imaging (MRI). m Tc-EC-neomycin and 99m Tc-EC-deoxyglucose were developed and their potential use in tumor characterization was evaluated. SUMMARY OF THE INVENTION The present invention overcomes these and other drawbacks of the prior art by providing a new radiolabeling strategy to target tissues for imaging. The invention provides radiolabeled tissue-specific ligands, as well as methods for making the radiolabeled ligands and for using them to image tissue-specific diseases. The present invention provides compositions for tissue specific disease imaging. The imaging compositions of the invention generally include a radionuclide label chelated with ethylenedicysteine and a tissue specific ligand conjugated to the ethylenedicysteine on one or both of its acid arms. The ethylenedicysteine forms an N 2 S 2 chelate with the radionuclide label. Of course, the chelated compound will include an ionic bond between the ranionuclide and the chelating compound. The terms "EC-tissue specific ligand conjugate," "EC-derivative" and "EC-drug conjugate" are used interchangeably herein to refer to the unlabeled ethylenedicysteine-tissue 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 Tc(V)O- complexes on the basis of efficient binding of the oxotechnetium group to two thiol-sulphur and two amine-nitrogen atoms. The pp "Tc labeled diethylester ( pp '"Tc-L,L-ECD) is known as a brain agent. PPm Tc-L,L-ethylenedicysteine ( p '"Tc-L,L-EC) is its most polar metabolite and was discovered to be excreted rapidly and efficiently in the urine. Thus, '"Tc-L,L-EC has been used as a renal function agent. (Verbruggen et al. 1992). 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, antimetabolite, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, 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 referred 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, BRCA1, 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 ampicillin, 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 polyamino 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 estradiol, 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 acid or aspartic acid. When the drug functional group is aliphatic or aromatic-NH 2 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 15,000), glutamic acid or aspartic acid. When the drug functional group is carboxylic acid or peptide, such as in methotrexate or folic acid, the linker may be ethylenediamine, or lysine. While the preferred radionuclide for imaging is p "Tc, it is envisioned that other radionuclides may be chelated to the EC-tissue specific ligand conjugates, or EC-drug conjugates of the mvention, especially for use as therapeutics. For example, other useful radionuclides are 188 Re, 186 Re, 153 Sm, 166 Ho, 90 Y, 89 Sr, 67 Ga, 68 Ga, m In, 153 Gd, and 59 Fe. These compositions are useful to deliver the therapeutic radionuclides to a specific lesion in the body, such as breast cancer, ovarian cancer, prostate cancer (using for example, 186/188 Re-EC-folate) and head and neck cancer (using for example, Re-EC-nitroimidazole). Specific embodiments of the present invention include Pm Tc-EC-annexin V, p '"Tc-EC- colchicine, 9Pm Tc-EC-nitroimidazole, 99m Tc-EC-glutamate pentapeptide, PPm Tc-EC- metronidazole, w Tc-EC-folate, "Tc-EC-methotrexate, pp Tc-EC-tomudex, pp " c-EC- neomycin, pp "Tc-EC-kanamycin, w Tc-EC-aminoglycosides, (glucosamine, EC-deoxyglucose), mTc-EC-gentamycin, and 00 '"τ c _EC-tobramycin. The present mvention further provides a method of synthesizing a radiolabeled 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, and admixing the EC -tissue specific ligand derivative with a radionuclide and a reducing agent to obtain a radionuclide labeled EC-tissue specific ligand derivative. The radionuclide is chelated to the EC via an N 2 S 2 chelate. 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, and reacting the drug conjugate with Tc in the presence of a reducing agent to form an N 2 S 2 chelate between the ethylenedicysteine and the p "Tc. 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 another embodiment, the present invention provides a method of imaging a site within a mammalian body. The imaging method includes the steps of administering an effective diagnostic amount of a composition comprising a p '"Tc labeled ethylenedicysteine-tissue specific ligand conjugate and detecting a radioactive signal from the '"Tc localized at the site. The detecting step will typically be performed from about 10 minutes to about 4 hours after introduction of the composition into the mammalian body. Most preferably, the detecting step will be performed about 1 hour after injection of the composition into the mammalian body. 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 mammalian 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 kit for preparing a radiopharmaceutical preparation. The kit generally includes a sealed 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 to label the conjugate with '"Tc. 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. Scavengers may also be present to bind leftover radionuclide. 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 rumor in the form of a labeled EC-drug conjugate and then imaging the site within hours to determine whether a particular drug. 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 mcludes a radionuclide chelated to 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 many anticancer agents known to be specific for certain types of cancers. However, not every anticancer agent for a specific 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 a scintigraphic imaging agent. The reagent of the invention includes a tissue specific ligand, having an affimty for targeted sites in vivo sufficient to produce a scintigraphically-detectable image, covalently linked to a P Tc binding moiety. The P m Tc binding moiety is either directly attached to the tissue specific ligand or is attached to the ligand through a linker as described above. The P m Tc binding moiety is preferably an N 2 S 2 chelate between m Tc in the +4 oxidation state and ethylenedicysteine (EC). The tissue specific ligand will be covalently linked to one or both acid arms of the EC, either directly or through a linker as described above. The tissue specific ligand may be any of the ligands as described above. BRIEF DESCRIPTION OF THE DRAWINGS The following 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 pp '"Tc-EC-folate. FIG. 2. Synthetic scheme of '"Tc-EC-MTX (methotrexate). FIG. 3. Synthetic scheme of Pm Tc-EC-TDX (tomudex). FIG. 4. Biodistribution studies for "Tc-EC and pp '"Tc-EC-folate. FIG. 5. Blocking studies for tumor/muscle and tumor/blood count ratios with '"Tc-EC-folate. FIG. 6A and 6B. Scintigraphic images of tumor in S Tc-EC-folate injected group as compared to p '"Tc-EC injected group. FIG. 7. Synthetic scheme of EC-MN (metronidazole) FIG. 8A and FIG. 8B. For EC-NIM, FIG. 8A shows the synthetic scheme and FIG. 8B illustrates the 1H-NMR confirmation of the structure. FIG. 9. Biodistribution studies (tumor/blood ratios) for pp "Tc-EC-MN, π A SF-mjTτ?τMs ΛτISoO a„„ndj r [l 1 3 J 1T]IMISO. FIG. 10. Biodistribution studies (tumor/muscle ratios) for p " ! Tc-EC, [ 18 F]FMISO and [ 131 I]IMISO. FIG. 11 A and 11 B. Scintigraphic images of tumor in PPm Tc-EC-MN (FIG. 11 A) and 99m Tc-EC (FIG. 1 IB) injected groups. FIG. 12. Autoradiograms performed at 1 hour after injection with p " ! Tc-EC-MN. FIG. 13. Illustrates stability of p '"Tc-EC-NIM in dog serum samples. FIG. 14A and FIG. 14B. Illustrates breast tumor uptake of pp "Tc-EC-NIM vs. p '"Tc- EC in rats (FIG. 14A) and in rats treated with paclitaxel compared to controls (FIG. 14B). FIG. 15A, FIG. 15B, FIG. 15C, and FIG. 15D. Illustrates ovarian tumor uptake of PPm Tc-EC-NIM vs. p '"Tc-EC in rats (FIG. 15 A) The tumor uptake in rats treated with paclitaxel (FIG. 15B) was less than tumor uptake in rats not treated with paclitaxel (FIG. 15 A). Also illustrated is tumor uptake of PP/ "Tc-EC-NIM in rats having sarcomas. FIG. 15C shows tumor uptake in sarcoma bearing rats treated with paclitaxel while FIG. 15D shows tumor uptake in rats not treated with paclitaxel. There was a decreased uptake of p '"Tc-EC-NIM after treatment with paclitaxel. FIG. 16. Synthetic scheme of EC-GAP (pentaglutamate). FIG. 17. Scintigraphic images of breast tumors in pp '"Tc-EC-GAP injected group. FIG. 18. Scintigraphic images of breast tumors in p '"Tc-EC- ANNEX V injected group at different time intervals. FIG. 19A and FIG. 19B. Comparison of uptake difference of P m Tc-EC-ANNEX V between pre- (FIG. 19 A) and post- (FIG. 19B) paclitaxel treatment in ovarian tumor bearing group. FIG. 20 A and FIG. 20B. Comparison of uptake difference of pp '"Tc-EC- ANNEX V between pre- (FIG. 20A) and post- (FIG. 20B) paclitaxel treatment in sarcoma tumor bearing group. FIG. 21. Synthetic scheme of EC-COL (colchicine). FIG. 22. Illustration that no degradation products observed in EC-COL synthesis. FIG. 23. Ratios of tumor to muscle and tumor to blood as function of time for p "Tc-EC-COL. FIG. 24. Ratios of tumor to muscle and tumor to blood as function of time for mTc-EC. FIG. 25. In vivo imaging studies in breast tumor bearing rats with p '"Tc-EC-COL. FIG. 26. In vivo imaging studies in breast tumor bearing rats with 99m n Tc-EC. FIG. 27. Computer outlined region of interest after injection of 99m " ! nTc-EC-COL vs p'"Tc-EC. FIG. 28. SPECT with pp '"Tc-EC-MN of 59 year old male patient who suffered stroke. Images taken one hour post-injection. FIG. 29. MRI Tl weighted image of same patient as FIG. 28. FIG. 30. SPECT with pp '"Tc-EC-MN of 73 year old male patient one day after stroke at one hour post-injection. FIG. 31. SPECT with PPw Tc-EC-MN of same 73 year old patient as imaged in FIG. 30 twelve days after stroke at one hour post-injection. FIG. 32. CT of same 73 year old male stroke patient as imaged in FIG. 30, one day after stroke. FIG. 33. CT of same 73 year old male stroke patient as imaged in FIG. 32, twelve days after stroke. Note, no marked difference between days one and twelve using CT for imaging. FIG. 34. SPECT with 99mTc-EC-MN of 72 year old male patient who suffered a stroke at one hour post-injection. FIG. 35. CT of same 72 year old stroke patient as imaged in FIG. 34. Note how CT image exaggerates the lesion size. FIG. 36. Synthetic scheme of 99mTc-EC-neomycin. FIG. 37A. Scintigraphic image of breast tumor-bearing rats after administration of P w Tc-EC and "Tc-EC-neomycin (100 μCi/rat, iv.) showed that the tumor could be well visualized from 0.5-4 hours postinjection. FIG. 37B. Scintimammography with pp "Tc-EC- neomycin (30 mCi, iv.) of a breast cancer patient. Images taken two hours post-injection. FIG. 38A. 1H-NMR of EC. FIG. 38B. 1H-NMR of neomycin. FIG. 38C. 1H-NMR of EC-neomycin. FIG. 39A and FIG. 39B. Mass spectrometry of EC-neomycin (M+ 1112.55). FIG. 40A. UV wavelength scan of EC. FIG. 40B. UV wavelength scan of neomycin. FIG. 40C. UV wavelength scan of EC-neomycin. FIG. 41. Radio-TLC analysis of P9 '"Tc-EC-neomycin. FIG. 42. HPLC analysis of P m Tc-EC-neomycin (radioactive detector). FIG. 43. HPLC analysis of pp "Tc-EC-neomycin (UV 254 nm). FIG. 44. HPLC analysis of ] 8 F-FDG (radioactive detector). FIG. 45. HPLC analysis of l 8 F-FDG (UV 254 nm). FIG. 46. In vitro cellular uptake assay of a series of p "Tc-EC-drug conjugates in lung cancer cell line. "Tc-EC- neomycin showed highest uptake in the agents tested. FIG. 47. Effect of glucose on cellular (A549) uptake of p " ! Tc-EC- neomycin and 18 F-FDG. FIG. 48A and FIG. 48B. Effect of glucose on cellular (H1299) uptake of P m Tc-EC 1 fi neomy cciinn aanndd 18 FF--FFDDGG iilllluussttrraatteed as percent of drug uptake (FIG. 48A) and as percent of change with glucose loading (FIG. 48B) FIG. 49. Synthetic scheme of ^" c-EC-Glucosamine FIG. 50. Hexokinase assay of glucose. FIG. 51. Hexokinase assay of glucosamine. FIG. 52. Hexokinase assay of EC-glucosamine. FIG. 53. Hexokinase assay of EC-GAP-glucosamine. FIG. 54. Synthetic scheme of "Tc-EC-GAP-glucosamine. FIG. 55 A, FIG. 55B, FIG. 55C. In vitro cellular uptake assay of '"Tc-EC (FIG. 56A), p " c-EC-deoxygmcose-GAP (FIG. 56B), and 18 F-FDG (FIG. 56C) in lung cancer cell line (A549). 99m Tc-EC-DG showed similar uptake compared to 18 F-FDG. FIG. 56. Tumor-to-tissue count density ratios of p "Tc-EC-GAP in breast tumor- bearing rats. FIG. 57 In vitro cellular uptake of PDG with glucose loading at 2 hours post- injection in breast cancer cell line (13762). FIG. 58. In vivo tissue uptake of p "Tc-EC-neomycin in breast tumor-bearing mice. FIG. 59. Synthetic scheme of pp "Tc-EC-deoxyglucose. FIG. 60. Mass spectrometry of EC-deoxyglucose. FIG. 61. 1H-NMR of EC-deoxyglucose (EC-DG). FIG. 62. 1 H-NMR of glucosamine. FIG. 63. Radio-TLC analysis of m Tc-EC-DG. FIG. 64. HPLC analysis of pp "Tc-EC-deoxyglucose and PPm Tc-EC- (radioactive detector). FIG. 65. HPLC analysis of "Tc-EC-deoxyglucose and p "'Tc-EC (radioactive detector, mixed). FIG. 66. Hexokinase assay of glucose. FIG. 67. Hexokinase assay of FDG. FIG. 68. Hexokinase assay of EC-DG. FIG. 69. In vitro cellular uptake assay of ^'"Tc-EC-deoxyglucose, vy '"Tc-EC and 7S F-FDG in lung cancer cell line (A549). P9 "'Tc-EC-DG showed similar • uptake compared to ;6 F-FDG. FIG. 70. Effect of d- and 1-glucose on breast cellular (13762 cell line) uptake of '"Tc-EC- DG. FIG. 71. Effect of d- and 1-glucose on breast cellular (13762 cell line) uptake of /δ F-FDG. FIG. 72. Effect of d- and 1-glucose on lung cellular (A549 cell line) uptake of ;s F- FDG. FIG. 73. Effect of d- and 1-glucose on breast cellular (A549 cell line) uptake of '"Tc-EC- DG. FIG. 74. Effect of in vivo blood glucose level induced by glucosamine and EC-DG (1.2 mmol/kg, i.v.). FIG. 75. Effect of in vivo blood glucose level induced by FDG (1.2 and 1.9 mmol/kg, i.v.) and insulin. FIG. 76. Tumor-to-tissue count density ratios of '"Tc-EC-deoxyglucose in breast tumor-bearing rats. FIG. 77. In vivo biodistribution of • 99m '" n Tc-EC-deoxyglucose in breast tumor-bearing rats. FIG. 78. In vivo tissue uptake of '"Tc-EC-deoxyglucose in lung tumor-bearing mice. FIG. 79. In vivo tissue uptake of PPw Tc-EC-neomycin in lung tumor-bearing mice. FIG. 80. In vivo tissue uptake of s F-FDG in lung tumor-bearing mice. FIG. 81. Planar image of breast tumor-bearing rats after administration of m Tc- EC and , "Tc-EC-deoxyglucose (100 μCi/rat, iv.) showed that the tumor could be well visualized from 0.5-4 hours postinjection. FIG. 82 A. MRI of a patient with malignant astrocytoma. FIG. 82B. SPECT with pp '"Tc-EC-DG of a patient with malignant astrocytoma. FIG. 83 A. MRI of a patient with hemorrhagic astrocytoma. FIG. 83B. SPECT with pp '"Tc-EC-DG of a patient with malignant astrocytoma. FIG. 84A. MRI of a patient with benign meningioma. FIG. 84B. SPECT with PPm Tc-EC-DG of a patient with benign meningioma showed no focal intensed uptake. FIG. 85A. CT of a patient with TB in lung. FIG. 85B. SPECT with p " c-EC-DG of a patient with TB showed no focal intensed uptake. FIG. 86A. CT of patient with lung cancer. FIG. 86B. Whole body images of pp "Tc-EC-DG of a patient with lung cancer. FIG. 86C. SPECT with PP Tc-EC-DG of a patient with lung cancer, the tumor showed focal intensed uptake. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS In the field of nuclear medicine, certain pathological conditions are localized, or their extent is assessed, by detecting the distribution of small quantities of internally-administered radioactively labeled tracer compounds (called radiotracers or radiopharmaceuticals). Methods for detecting these radiopharmaceuticals are known generally as imaging or radioimaging methods. In radioimaging, the radiolabel is a gamma-radiation emitting radionuclide and the radiotracer is located using a gamma-radiation detecting camera (this process is often referred to as gamma scintigraphy). The imaged site is detectable because the radiotracer is chosen either to localize at a pathological site (termed positive contrast) or, alternatively, the radiotracer is chosen specifically not to localize at such pathological sites (termed negative contrast). A variety of radionuclides are known to be useful for radioimaging, including 67 Ga, pp '"Tc, m In, 123 1, 125 1, 169 Yb or 186 Re. Due to better imaging characteristics and lower price, attempts have been made to replace the I, I, Ga and In labeled compounds with corresponding P Tc labeled compounds when possible. Due to favorable physical characteristics as well as extremely low price ($0.21/mCi), pp '"Tc has been preferred to label radiopharmaceuticals. Although it has been reported that DTPA-drug conjugate could be labeled with p '"Tc effectively (Mathias et al, 1997), DTPA moiety does not chelate with pp '"Tc as stable as with ι n In. (Goldsmith, 1997). A number of factors must be considered for optimal radioimaging in humans. To maximize the efficiency of detection, a radionuclide that emits gamma energy in the 100 to 200 keV range is preferred. To minimize the absorbed radiation dose to the patient, the physical half-life of the radionuclide should be as short as the imaging procedure will allow. To allow for examinations to be performed on any day and at any time of the day, it is advantageous to have a source of the radionuclide always available at the clinical site. p '"Tc is a preferred radionuclide because it emits gamma radiation at 140 keV, it has a physical half-life of 6 hours, and it is readily available on-site using a molybdenum-99/technetium-P w generator. Bis-aminoethanethiol tetradentate ligands, also called diaminodithiol compounds, are known to form very stable Tc(V)O-complexes on the basis of efficient binding of the oxotechnetium group to two thiolsulfur and two amine nitrogen atoms. (Davison et al, 1980;1981; Verbruggen et al, 1992). p "Tc-L,L-ethylenedicysteine ( p '"Tc-EC) is the most recent and successful example of N 2 S chelates. (Verbruggen et al, 1992; Van Nerom et al., 1993; Surma et al, 1994). EC, a new renal imaging agent, can be labeled with p '"Tc easily and efficiently with high radiochemical purity and stability and 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 with galium-68 (a positron emitter, tl/2 = 68 minutes) for PET and gadolinium, iron or manganese for magnetic resonance imaging (MRI). The present invention utilizes m Tc-EC as a labeling agent 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 radioactive signal over the area of interest. While it is envisioned that the use of pp " ! Tc-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 Pm Tc-EC-drug 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. Radiolabeled proteins and peptides have been reported in the prior art. (Ege et al, U.S. Patent No. 4,832,940, Abrams et al, 1990; Bakker et al., 1990; Goldsmith et al., 1995, 1997; Olexa et al. 1982; Ranby et al. 1988; Hadley et al. 1988; Lees et al. 1989; Sobel et al. 1989; Stuttle, 1990; Maraganore et al. 1991; Rodwell et al. 1991; Tubis et al. 1968; Sandrehagen 1983). However, pp '"Tc-EC has not been used in conjunction with any ligands, other than as the diethylester (Kabasakal, 2000), prior to the present invention. The diethylester of EC was used as a cerebral blood flow agent (Kikukawa, et al, 2000). Although optimal for radioimaging, the chemistry of P Tc has not been as thoroughly studied as the chemistry of other elements and for this reason methods of radiolabeling with PPm Tc are not abundant. p '"Tc is normally obtained as " ! Tc pertechnetate (TcO " ; technetium in the +7 oxidation state), usually from a molybdenum-99/technetium-PP77z generator. However, pertechnetate does not bind well with other compounds. Therefore, in order to radiolabel a compound, pp "'Tc pertechnetate must be converted to another form. Since technetium does not form a stable ion in aqueous solution, it must be held in such solutions in the form of a coordination complex that has sufficient kinetic and thermodynamic stability to prevent decomposition and resulting conversion of p "Tc either to insoluble technetium dioxide or back to pertechnetate. For the purpose of radiolabeling, it is particularly advantageous for the P9m Tc complex to be formed as a chelate in which all of the donor groups surrounding the technetium ion are provided by a single chelating ligand - in this case, ethylenedicysteine. This allows the chelated '"Tc to be covalently bound to a tissue specific ligand either directly or through a single linker between the ethylenedicysteine and the ligand. Technetium has a number of oxidation states: +1, +2, +4, +5, +6 and +7. When it is in the +1 oxidation state, it is called Tc MIBI. Tc MIBI must be produced with a heat reaction. (Seabold et al. 1999). For purposes of the present invention, it is important that the Tc be in the +4 oxidation state. This oxidation state is ideal for forming the N 2 S chelate with EC. Thus, in forming a complex of radioactive technetium with the drug conjugates of the invention, the technetium complex, preferably a salt of p '"Tc pertechnetate, is reacted with the drag conjugates of the invention in the presence of a reducing agent. The preferred reducing agent for use in the present invention is stannous ion in the form of stannous chloride (SnCl 2 ) to reduce the Tc to its +4 oxidation state. However, it is contemplated that other reducing agents, such as dithionate ion or ferrous ion may be useful 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 preferable, for example, to use from about 10 to about 100 μg SnCl per about 100 to about 300 mCi of Tc pertechnetate. The most preferred amount is about 0.1 mg SnCl 2 per about 200 mCi of Tc pertechnetate and about 2 ml saline. This typically produces enough Tc-EC-tissue specific ligand conjugate for use in 5 patients. 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, thiamine 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 and labeled with pp '"Tc 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 mvention include, but are not limited to, angiogenesis/antiangiogenesis ligands, DNA topoisomerase inhibitors, glycolysis markers, antimetabohte 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 ligand 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 1 Drug Functional Group Linker Example Aliphatic or phenolio-OH EC-Poly (glutamic acid) A (MW. 750-15,000) or EC. poly(aspertic acid) (MW. 2000-15,000) or bromo ethylacetate or EC-glutamic acid or EC-aspertic acid. Aliphatic or aromatic-ΝH 2 EC-poly(glutamic acid) B or peptide (MW. 750-15,000) or EC- poly(aspertic acid) (MW. 2000-15,000) or EC- glutamic acid (mono- or diester) or EC-aspartic acid. Carboxylic acid or peptide Ethylene diamine, lysine C Examples: A. estradiol, topotecan, paclitaxel, raloxlfen etoposide B. doxorubicin, mitomycin C, endostatin, annexin V. LHRH, octreotide, VIP C. methotrexate, folic acid It is also envisioned that the EC-tissue specific ligand drug conjugates of the mvention may be chelated to other radionuclides and used for radionuclide therapy. Generally, it is believed that virtually any α, β-emitter, γ-emitter, or β, γ-emitter can be used in conjunction with the mvention. Preferred β, γ-emitters include 166 Ho, 188 Re, 186 Re, 153 Sm, and 89 Sr. Preferredβ- emitters include 90 Y and 25 Ac. Preferred γ-emitters include 67 Ga, 68 Ga, 6 Cu, 62 Cu and Preferred α-emitters include 2 At and 212 Bi. It is also envisioned that para-magnetic substances, such as Gd, Mn and Fe can be chelated with EC for use in conjunction with the present invention. 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 to label the conjugate with Pm Tc. p '"Tc labeled scintigraphic imaging agents according to the present invention can be prepared by the addition of an appropriate amount of p '"Tc or p "Tc complex into a vial containing the EC-tissue specific ligand conjugate and reducing agent and reaction under conditions described in Example 1 hereinbelow. 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. Radioactively labeled reagents or conjugates provided by the present invention are provided having a suitable amount of radioactivity. In forming p '"Tc radioactive complexes, it is generally preferred to form radioactive complexes in solutions containing radioactivity at concentrations of from about 0.01 millicurie (mCi) to about 300 mCi per mL. p p '"Tc labeled scintigraphic imaging agents provided by the present invention can be used for visualizing sites in a mammalian body. In accordance with this invention, the p '"Tc labeled scintigraphic imaging agents are administered in a single unit injectable dose. Any of the common carriers known to those with skill in the art, such as sterile saline solution or plasma, can be utilized after radiolabeling for preparing the injectable solution to diagnostically image various organs, tumors and the like in accordance with this invention. Generally, the unit dose to be administered has a radioactivity of about 0.01 mCi to about 300 mCi, preferably 10 mCi to about 200 mCi. The solution to be injected at unit dosage is from about 0.01 mL to about 10 mL. After intravenous administration, imaging of the organ or tumor in vivo can take place, if desired, in hours or even longer, after the radiolabeled reagent is introduced into a patient. In most instances, a sufficient amount of the administered dose will accumulate in the area to be imaged within about 0.1 of an hour to permit the taking of scintiphotos. Any conventional method of scintigraphic imaging for diagnostic or prognostic purposes can be utilized in accordance with this invention. The " ! Tc-EC labeling strategy of the invention may also be used for prognostic purposes. It is envisioned that EC may be conjugated to known drags of choice for cancer chemotherapy, such as those listed in Table 2. These EC-drag conjugates may then be radio labeled with '"Tc and administered to a patent having a tumor. The labeled EC-drug conjugates will specifically bind to the tumor. Imaging may be performed to determine the effectiveness of the cancer chemotherapy drag 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 drag can be determined. The pp '"Tc 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 radiolabeled 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 cell 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). Furthermore, bispecific antibodies that contain anti-FR antibodies 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 radiolabeled folate-conjugates, such as 67 Ga-deferoxamine-folate and 111 In-DTPA-folate 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 p "Tc-EC-folate, p '"Tc-EC-methotrexate ( PPm Tc-EC-MTX), pp '"Tc-EC-tomudex ( p '"Tc-EC-TDX). Tumor Hypoxia Targeting Tumor cells are more sensitive to conventional radiation in the presence of oxygen than in its absence; even a small percentage of hypoxic cells within a tumor could limit the response to radiation (Hall, 1988; Bush et al, 1978; Gray et al, 1953). Hypoxic radioresistance has been demonstrated in many animal tumors but only in few tumor types in humans (Dische, 1991; Gatenby et al, 1988; Nordsmark et al, 1996). 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 with different radioisotopes (e.g., 18 F, 123 I, p '"Tc) may be useful for differentiating a hypoxic but metabolically active tumor from a well-oxygenated active tumor by PET or planar scintigraphy. [ 18 F]Fluoromisonidazole (FMISO) has been used with PET to evaluate tumors hypoxia. Recent studies have shown that PET, with its ability to monitor cell oxygen content through [ 18 F]FMISO, has a high potential to predict tumor response to radiation (Koh et al, 1992; Valk et al, 1992; Martin et al, 1989; Rasey et al, 1989; Rasey et al, 1990; Yang et al, 1995). PET gives higher resolution without collimation, however, the cost of using PET isotopes in a clinical setting is prohibitive. Although labeling MISO with iodine was the choice, high uptake in thyroid tissue was observed. Therefore, it is desirable to develop compounds for planar scintigraphy that the isotope is less expensive and easily available in most major medical facilities. In this invention, the inventors present the synthesis of '"Tc- EC-2- nitroimidazole and "Tc-EC-metronidazole and demonstrate their potential use as tumor hypoxia markers. Peptide Imaging of Cancer Peptides and amino acids have been successfully used in imaging of various types of tumors (Wester et al, 1999; Coenen and Stocklin, 1988; Raderer et al, 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 Hilxner, 1981). Glutamic acid based peptide has been used as a drag 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. The polyglutamate is then re- conjugated to folate to form folyl polyglutamate, which is involved in glucose metabolism. 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 and 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; Blakenberg et al, 1998; Blakenberg et al, 1999; Tait 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 useful to evaluate the efficacy of therapy such as disease progression or regression. In this invention, the inventors synthesize p '"Tc-EC-annexin 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 drags. 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 are considered as microtubule inhibitors or as spindle poisons (Lu, 1995). Many classes of antimitotic compounds control microtubule assembly-disassembly by binding to tubulin (Lu, 1995; Goh et al, 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 et al, 1998; Wang et al, 1998). Among colchicinoids, colchicine is an effective anti- inflammatory drag 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 pp '"Tc-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, '"Tc-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 radiosensitizers or 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 drag resistance. To correlate the imaging findings with the overexpression of P53 by histopathology before and after chemotherapy would be useful in following-up tumor treatment response. p '"Tc-EC-2-nitroimidazole and p '"Tc-EC-metronidazole were developed. 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 are considered as microtubule inhibitors or as spindle poisons. Colchicine, a potent antiangiogenic agent, is known to inhibit microtubule polymerization and cell anest at metaphase. Colchicine (COL) may be useful as a biochemical tool to assess cellular functions. pp "Tc-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 '"Tc-EC-metronidazole ( '"Tc-EC-MN). Metronidazole is a tumor hypoxia marker. Tissue in the area of a stroke becomes hypoxic due to lack of oxygen. The SPECT images were conducted at 1 and 3 hours post injection with 9P '"Tc-EC-MN. 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. Case 1. A 59 year old male patient suffered a stroke in the left basal ganglia. SPECT P m Tc-EC-MΝ identified the lesions at one hour post-injection (FIG. 28), which corresponds to MRI Tl weighted image (FIG. 29). Case 2. A 73 year old male patient suffered a stroke in the left medium cerebral artery (MCA) territory. SPECT p '"Tc-EC-MN was obtained at day 1 and day 12 (FIGs. 30 and 31) at one hour post-injection. The lesions showed significant increased uptake at day 12. CT showed extensive cerebral hemorrhage in the lesions. No marked difference was observed between days 1 and 12 (FIGs. 32 and 33). The findings indicate that the patient symptoms improved due to the tissue viability (from anoxia to hypoxia). SPECT PPm Tc-EC-MN provides functional information which is better than CT images. Case 3. A 72 year old male patient suffered a stroke in the right MCA and PCA area. SPECT "'Tc-EC-MΝ identified the lesions at one hour post-injection (FIG. 34). CT exaggerates the lesion size. (FIG. 35). Tumor Glycolysis Targeting The radiolabeled 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; Fanciulli 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; Moller 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-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 1H-NMR and fast-atom bombardment mass spectroscopy (FAB-MS). Synthesis of aminoethylamido analogue of methotrexate (MTX- NH 2 ) MIX (227 ma, 0.5 mmol) was dissolved in 1 ml of HCI solution (2N). The pH value was <3. To this stined solution, 2 ml of water and 4 ml of N-ethoxycarbonyl-2-ethoxy-l,2- dihydroquinoline (EEDQ, 6.609% in methanol, 1 mmol) were added at room temperature. Ethylenediamine (EDA, 0.6 ml, 10 mmol) was added slowly. The reaction mixture was stined overnight and the solvent was evaporated in vacuo. The raw solid material was washed with diethyl ether (10 ml), acetonitrile (10 ml) and 95% ethyl alcohol (50 ml) to remove the unreacted EEDQ and EDA. The product was then dried by lyophilization and used without further purification. The product weighed 210 mg (84.7% ) as a yellow powder, m.p. of product: 195-198 °C (dec, MIX); 1H-NMR (D 2 O) δ 2.98-3.04 (d, 8H, - (CH 2 ) 2 CONH(CHo) 2 NH 2 ), 4.16- 4.71 (m, 6H, -CH 2- pteridinyl, aromatic-NCH 3 , NH-CH-COOH glutamate), 6.63-6.64 (d, 2H, aromatic-CO), 7.51-753 (d, 2H. aromatic-N), 8.36 (s, IH, pteridinyl). FAB MS m/z calcd for C 22 H 28 ,N 10 ,O 4 (M) + 496.515, found 496.835. Synthesis of aminoethylamido analogue of folate (Folate- ΝH 2 ) 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 stined solution, N-ethoxycarbonyl-2-ethoxy-l,2- dihydroquinoline (EEDQ, 1 g in 10 ml methanol, 4.0 mmol) and ethylenediamine (EDA, 1.3 ml, 18 mmol) were added slowly. The reaction mixture was stined 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). 1H-NMR (D 2 O) δl.97-2.27 (m, 2H, -CH 2 glutamate of folate), 3.05-3.40 (d, 6H, -CH 2 COΝH(CH2)2NH 2 ), 4.27-4.84 (m, 3H, -CH 2 -pteridinyl, NH-CH-COOH glutamate), 6.68-6.70 (d, 2H, aromatic-CO), 7.60-7.62 (d, 2H, aromatic-N), 8.44 (s, IH, pteridinyl). FAB MS m/z calcd for C 21 H 25 N 9 ,O 5 (M) + 483, found 483.21. Synthesis of ethylenedicysteine- folate (EC- Folate) To dissolve EC, NaOH (2N, 0.1 ml) was added to a stined solution of EC (114 ma, 0.425 mmol) in water (1.5 ml). To this colorless solution, sulfo-ΝHS (92.3 mg, 0.425 mmol) and EDC (81.5 mg, 0.425 mmol) were added. Folate-NH 2 (205 mg, 0.425 mmol) was then added. The mixture was stined 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); 1H-NMR (D 2 O) δl.98-2.28 (m, 2H, -CH2 glutamate of folate), 2.60-2.95 (m, 4H and -CH 2 -SH of EC). 3.24-3.34 (m, 10H, -CH 2 -CO, ethylenediamine of folate and ethylenediamine of EC), 4.27-4.77 (m, 5H, -CH-pteridinyl, NH-CH-COOH glutamate 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 C29H37N u S 2 O 8 Na 2 (8H 2 O), 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. Radiolabeling of EC-folate and EC with 9P, "Tc Radiosynthesis of m Tc- EC-folate was achieved by adding required amount of PPm Tc-pertechnetate into home-made kit containing the lyophilized residue of EC-folate (3 mg), SnCl 2 (100 μg), Na 2 HPO 4 (13.5 mg), ascorbic acid (0.5 mg) and NaEDTA (0.5 mg). Final pH of preparation was 7.4. p "Tc-EC was also obtained by using home-made kit containing the lyophilized residue of EC (3 mg), SnC . (100 μg), Na 2 ,IPO 4 (13.5 mg), ascorbic acid (0.5 mg) and NaEDTA (0.5 mg) at pH 10. Final pH of preparation was then adjusted to 7.4. Radiochemical purity was determined by TLC (ITLC SG, Gelman Sciences, Ann Arbor, MI) eluted with, respectively, acetone (system A) and ammonium acetate (IM in water) :methanol (4:1) (system B). From radio-TLC (Bioscan, Washington, DC) analysis, the radiochemical purity was >95% for both radiopharmaceuticals. Radio-TLC data are summarized in Table 2. Synthesis of p "'Tc-EC-folate is shown in FIG. 1. TABLE 2 DRUGS OF CHOICE FOR CANCERCHEMOTHERAPY The tables that follow list drags used for treatment of cancer in the USA and Canada and their major adverse effects. The Drags 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 drags and their adverse effects follow. For purposes of the present invention, these lists are meant to be exemplary and not exhaustive. DRUGS OF CHOICE Cancer Drugs of Choice Some alternatives Adrenocortical** Mitotane Doxorubicin, streptozocin, Cisplatin etoposide Cancer Drugs of Choice Some alternatives Bladder* Local: Instillation of BCG Instillation of mitomycin, Systemic: Methotrexate + vinblastine doxorubicin or thiotape + doxorubicin + claplatin (MVAC) Pecitaxel, substitution of Claplatin + Methotrexate + carboplatin for claplatin in vinblastine (CMV) combinations Brain Anaplastic astrocytoma* Procarbazine + lamuatine + Carmustine, Claplatin Anaplastic oligodendro- vincristine Carmustine, Claplatin Giloma* Procarbazine + lamustine + Gilabiastome vincristine Procarbazine, claplatin Medulloblastoma Etoposide Carmustine or lamustine Vincristine + carmustine ± mechiorethamine ± methotrexate Mechiorethamine + vincristine + procarbazine + prednisone (MOPP) Vincristine + claplatin ± cyclophosphamide Primary central nervous Methotrexate (high dose Intravenous system lymphoma and/or lhtrathecal) ± cytarabine (Intravenous and/or lhtrathecal) Cyclophosphamide + Doxorubicin + vincristine + prednisone (CHOP) Breast Adjuvant 1 : Cyclophosphamide + methotrexate + fluorouracil (CMF); Cyclophosphamide 4- Doxorubicin ± fluorouracil (AC or CAF); Tamoxifen Metastatic: Cyclophosphamide + Paclitaxel; thiotepa + metho-trexate + fluorouracil (CMF) Doxorubicin + vinor Cyclophosphamide + duxorubicin blastine; mitomycin + ± fluorouracil (AC or CAF) for vinblastine; mitomycin + receptor-negative and/or hormone- methotrexate + refractory; Tamoxifen for receptor- mitoxantrone; fluorouracil positive and/or hormone-sensitive 2 by continuous infusion; Bone marrow transplant 3 Cervix** Claplatin Chlorambucil, vincristine, Ifosfamide with means fluorouracil, Doxorubicin, Bleomycin + ifosfamide with means methotrexate, altretamine Chemotherapy has only moderate activity. Chemotherapy has only minor activity. 1 Tamoxifen with or without chemotherapy is generally recommended for postmenopausal estrogen-receptor-positive, mode-positive patients and chemotherapy with or without tamoxifen for premenopausal mode-positive patients. Adjuvant treatment with chemotherapy and/or tamoxifen is recommended for mode-negative patients with larger tumors or other adverse prognostic indicators. Megastrol and other hormonal agents may be effective in some patients with tamoxifen fails. 3 After high-dose chemotherapy (Medical Letter, 34:79, 1982). Cancer Drugs of Choice Some alternatives + claplatin Chorlocarcinoma Methotrexate ± leucovorin Methotrexate + Dactinomycin dactinomycin + cyclophosphamide (MAC) Etoposide + methotrexate + dactinomycin + cyclophosphamide + vincristine Colorectal* Adjuvant colon 4 : Fluorouracil + Hepatic metastases: levam-isole; fluorouracil + Intrahepatic-arterial leucovorin floxuridine Metastatic: fluorouracil + leucovorin Mitomycin Embryonal rhabdomyosar- Vincristine + dectinomycin ± Same + Doxorubicin coma 5 cyclophas-phamide Vincristine + ifosfamide with means + etoposide Endometrial** Megastrol or another progestin fluorouracil, tamoxifen, Doxorubicin + claplatin ± altretamine cyclophos-phamide Esophageal* Claplatin + fluorouracil Doxorubicin, methotraxate, mitomycin Ewing's sarcoma 5 Cyclophosphamide (or ifosfamide CAV + etoposide with means) + Doxorubicin + vincristine (CAV) ± dactinomycin Gastric** Fluorouracil ± leucavorin Claplatin Doxorubicin, etoposide, methotrexate + leucovorin, mitomycin Head and neck squambus Claplatin + fluorouracil Blomycin, carboplatin, cell* 6 Methotrexate paclitaxel Islet cell** Streptozocin + Doxorubicin Streptozocin + fluorouracil; chlorozotochv 1 ; octreotide Kaposi's sarcoma* (Aids- Etoposide or interferon alfa or Vincristine, Doxorubicin, related) vinblastine bleomycin Doxorubicin + bleomycin + vincristine or vinblastine (ABV) Leukemia Acute lymphocytic Induction: Vincristine + prednisone Induction: same ± high- leukemia (ALL) 7 + asparaginase ± daunorubicin dose methotrexate ± For rectal cancer, postoperative adjuvant treatment with fluoroutacil plus radiation, preceded and followed by treatment with fluorouracil alone. 5 Drags have major activity only when combined with surgical resection, radiotherapy or both. 6 The vitamin A analog lactratinoln (Acgutana) can control pre-neoplastic lesions (leukoplakla) and decreases the rate of second primary tumors (SE Banner et al, J Natl Cancer Inst, 88:140 1994). Available in the USA only for investigational use. Cancer Drugs of Choice Some alternatives CNS prophylaxis: Intrathecal cyterabine; pegaspargase methotrexate ± systemic high-dose instead of asparaginese methotrexate with leutovorin ± Teniposide or etoposide Intrathecal cytarabine ± Intrathecal High-dose cytarabine hydrocortisone Maintenance: Methotrexate + Maintenance: same + mercapto-purine periodic vincristine + Bone marrow transplant. 3 8 prednisone Acute myeloid leukemia Induction: Cytsrabine + either Cytarabine + mitoxentrone (AML) 9 daunorubicin or idarubicin High-dose cyterabine Post Induction: High-dose cytarabine ± other drugs such as etoposide Bone marrow transplant 3 . Chronic lymphocytic Chlorambucil ± prednisone Cladribine, leukemia (CLL) Fludarabin cyclophosphamide, pentostatin, vincristine, Doxorubicin Chronic myeloid leukemia (CML) 10 Chronic phase Bone marrow transplant 3 Busulfan Interferon alfa Hydroxyures Accelerated" Bone marrow transplant 3 Hydroxyures, busulfen Blast crisis" Lymphoid: Vincristine + prednisone + L- Tretinoln + separaginess + intrathecal methotrexate (± Amsecrine, * azacitidine maintenance with methotrexate + 8- Vincristine ± plicamycin 7 High-risk patients (e.g., high counts, cytogenetic abnormalities, adults) may require additional drags for induction, maintenance and "Intensificiation" (use of additional drags after achievement of remission). Additional drags include cyclophosphamida, mitoxantrone and thloguanine. The results of one large controlled trial in the United Kingdom suggest that Intensificiation may improve survival in all children with ALL (JM Chasselle et al, Lancet, 34B:143, Jan 21, 1995). Patients with a poor prognosis initially or those who relapse after remission. 9 Some patients with acute promyelocytic leukemia have had complete responses to tratinoin. Such treatment can cause a toxic syndrome characterized primarily by fever and respiratory distress (RP Warrell, Jr et al, N Engl J Med. 328:177, 1993). 10 Allogeheic HLA-identical sibling bone manow transplantation can cure 40% to 70% of patients with CML in chronic phase, 18% to 28% of patients with accelerated phase CML, and < 15%) patients in blast crisis. Disease-free survival after bone manow transplantations adversely influenced by age > 50 years, duration of disease > 3 years from diagnosis, and use of one- antigen-mismatched or matched-unrelated donor manow. interferon also may be curative in patients with chronic phase CML who achieve a complete cytogenetic response (about 10%); it is the treatment of choice for patents > 80 years old with newly diagnosed chronic phase CML and for all patients who are not candidates for an allgensic bone manow transplant. Chemotherapy alone is palliative. 11 If a second chronic phase is achieved with any of these combinations, allogeneic bone manow transplant should be considered. Bone marrow transplant in second chronic phase may be curative for 30% to 35% of patients with CML. Cancer Drugs of Choice Some alternatives marcaptopurine) Hairy cell Leukemia Pentostatin or cladribine Interferon alfa, chlorambucil, fludarabin Liver* Doxorubicin Intrahepatic-arterial floxuridine Fluorouracil or claplatin Lung, small cell (cat cell) Claplatin + etoposide (PE) Ifosfamide with means + Cyclophosphamide + doxorubicin + carboplatin + etoposide (ICE) vincristine (CAV) Daily oral etoposide PE alternated with CAV Etoposide + ifosfamide with Cyclophosphamide + etoposide + claplatin means + claplatin (VIP (CEP) Paclitaxel Duxorubicin + cyclophosphamide + etoposide (ACE) Lung Claplatin + etoposide Claplatin + fluorouracil + (non-small cell) ** Claplatin + Vinblastine ± mitomycin leucovorin Claplatin + vincrisine Carboplatin + paclitaxel Lymphomas Hodgkin's 12 Doxorubicin + bleomycin + vinblastine + Mechlorethamine + vincristine + dacarbazine (ABVD) procarbazine + prednisone ABVD alternated with MOPP (MOPP) Mechlorethamine + vincristine + Chlorambusil + vinblastine + procarbazine (± prednisone) + doxorubicin + procarbazine + prednisone ± bleomycin + vinblastine (MOP[P]-ABV) carmustine Etoposide + vinblastine + doxorubicin Bone marrow transplant 3 Non-Hodgkin's Burkitt's lymphoma Cyclophosphamide + vincristine + Ifosfamide with means methotrexate Cyclophosphamide + Cyclophosphamide + high-dose cytarabine ± doxorubicin + vincrletine + methotrexate with leutovorin prednisone (CHOP) Intrathecal methotrexate or cytarabine Difuse large-cell lymphoma Cyclophosphamide + doxorubicin + Dexamethasone sometimes vincristine + prednisone (CHOP) substituted for prednisone Other combination regimens, which may include methotrexate, etoposide, cytarabine, bleomycin, procarbazine, ifosfamide and mitoxantrone Bone marrow transplant 3 Follicular lymphoma Cyclophosphamide or chlorambusil Same ± vincristine and prednisone, ± etoposide Interferon alfa, cladribine, fludarabin Bone marrow transplant 3 Cyclophosphamide + doxorubicin + vincristine + prednisone (CHOP) Melanoma** Interferon Alfa Carmustine, lomustine, cisplatin Dacarbazine Dacarbazine + clapletin + carmustine + tamoxifen Aldesleukin Mycosis fungoides* PUVA (psoralen + ultraviolet A) Isotretinoin, topical carmustine, Mechlorethamine (topical) pentosistin, fludarabin, Interferon alfa cladribine, photopheresis (extra- 12 Limited-stage Hodgkin's disease (stages 1 and 2) is curable by radiotherapy. Disseminated disease (stages 3b and 4) require chemotherapy. Some intermediate stages and selected clinical situations may benefit from both. Cancer Drugs of Choice Some alternatives Electron beam radiotherapy corporeal photochemitherapy), Methotrexate chemotherapy as in non- Hodgkm's lymphoma Mysloma* Melphelan (or cyclophosphamide) + Interferon alfa predmsons Bone marrow transplant 3 Melphalan ± carmustme + High-dose dexamethasons cyclophosphamide + predmsons + vincnstme Dexamethasone + doxorubicin + vincnstme (VAD) Vmcristme + carmustme + doxorubicin + predmsons (VBAP) Neuroblestoma* Doxorubicin + cyclophosphamide + Carboplatm, etoposide claplatin + teniposide or etoposide Bone marrow transplant 3 doxorubicin + cyclophosphamide Claplatin + cyclophosphamide Osteogemc sarcoma Doxorubicin + claplatin ± etopside ± Ifosfamide with means , ifosfamide etoposide, carboplatm, high- dose methotrexate with leucovorin Cyclophosphamide + etoposide Cancer Drugs of Choice Some alternatives Ovary Claplatin (or carboplatm) + paclitaxel Ifosfamide with means , Claplatin (or carboplatin) + paclitaxel , tamoxifen, cyclophosphamide (CP) ± doxorubicin melphalan, altretamine (CAP) Pancreatic Fluoroutacil ± leucovorm Gemoltabmet Prostate Leupro de (or goserelln) ± flutamide Estramustme ± vinblastine, aminoglutefhimide + hydrocortleone, estramustme + etoposide, diethylstllbestrol, mlutamide Renal ** Aldesleukrn Vinblastine, floxuridine Inteferon alfa Retinoblestoma 5* Doxorubicin + cyclophosphamide ± Carboplatm, etoposide, claplatin ± etoposide ± vincπstina Ifosfamide with means Sarcomas, soft tissue, adult * Doxorubicin ± decarbazine ± Mitornyeln + doxorubicin + cyclophosphamide ± Ifosfamide with claplatin means Vincπstina, etoposide Testicular Claplatin + etoposide + bleomycin Vmblestine (or etoposide) + (PEB) Ifosfamide with means + claplatin (VIP) Bone marrow transplant 3 Wilms' tumor Dectinomycln + vincriatine ± Ifosfamide with means , doxorubicin + cyclophosphamide etoposide, carboplatm + Available in the USA only for mvestigational use ANTICANCER DRUGS AND HORMONES Drug Acute Toxicity J Delayed toxicity J Aldesleukin (Interleukin-2; Fever; fluid retention; hypertension; Neuropsychiatric Proleukin - Cetus respiratory distress; rash; anemia; disorders; hypothyrldiam; Oncology) thrombocytophenia; nausea and nephrotic syndrome; vomiting; diarrhea; capillary leak possibly acute syndrome; naphrotoxlolty; leukoencaphalopathy; myocardial toxicity; hepatotoxicity; brachial plexopathy; bowel erythema nodosum; neutrophil perforation chemotactic defects Altretamine (hexamethyl- Nausea and vomiting Bone marrow depression; melamine; Hexalen ■ CNS depression; U Bioscience) peripheral neuropathy; visual hallucinations; stexis; tremors, alopecia; rash Aminogiutethimide Drowsiness; nausea; dizziness; rash Hypothryroidism (rare); (Cytadren - Ciba) bone marrow depression; fever; hypotension; mascullinization f Amsacrine (m-AMSA; Nausea and vomiting; diarrhea; pain Bone marrow depression; amaidine; AMSP P- or phlebitis on infuelon; anaphylaxia hepactic injury; D-Parke-Davis, convulsions; stomatitle; Amsidyl- Warner- ventricular fibrillation; Lambert) alopecia; congestive heart failure; renal dysfunction Asparaginase (Elspar- Nausea and vomiting; fever; chills; CNS depression or merck; Kidrolase in headache; hypersensitivity, hyperexcitability; acute Canada) anaphylexia; abdominal pain; hemorrhagic pancreatitis; hyperglycemia leading to coma coagulation defects; thromboals; renal damage; hepactic damage Cervix ** Claplatin Ifosfamide with means Chlorambucil, vincristine, Bleomycin patin fluoroutacil, doxorubicin, Ifosfamide with means methotrexete, altretamine Chorlocarcinoma Methotrexete ± leucovorin Methotrexete + Dactinomyclin dectinomycin + cyclophosphamide (MAC) Etoposide + methotrexate + dactinomycin + cyclophosphamide + vincriatine Colorectal * Adjuvant colon 4 : Fluoroutacil + Hepatic metastases: lavamleole; fluoroutacil + leucovarin Intrahepactic-arterial Metastatic: Fluoroutacil + leucvarin floxuridine Mitomyclin Embryonal Vincriatine + dectinomycin ± Same + doxorubicin rhebdomyosarcoma 6 cyclophosphamide Vincristine + Ifosfamide with means + etoposide Endometrial ** Megastrol or another progeetin Fluoroutacil, tamoxifen, Doxorubicin + claplatin + altretamine cyclophosphamide Cancer Drugs of Choice Some alternatives Esophageal * Claplatin + Fluoroutacil Doxorubicin, Ewing's sarcoma 5 Cyclophosphamide (or ifosfamide methotrexete, mitomycin with means ) + doxorubicin + CAV + etoposide vincrietine (CAV) ± dectinomycin Gastric Fluoroutacil ± leucovoin Claplatin, doxorubicin, etoposide, methotrexete +leucovorin, mitomycin Head and neck squamous Claplatin + fluoroutacil Blaonycin, carboplatin, cell *5 Methotrexete paciltaxel Islet call Streptozocin + doxorubicin Streptozocin + fluoroutacil; chlorozotocin; actreatide Kaposal's sercoma* Etoposide or Interferon alfa or Vincristine, doxorubicin, (AIDS-related) vinbleomycin stine bleomycin Doxorubicin + bleomycin + vincristine or vinbleomycin stine (ABV) Leukemias Induction: Vincristine + prednisone Industion: same + high- Acute lymphocytic + asparaginase ± daunorubieln dose methotrexete ± leukemia (ALL) 7 CNS prophylaxia; Intrathecal cyterabine; pegaspargase methotrexete ± systemic high-dose instead of aspareginese methotrexete with leucovorin + Teniposide or etoposide Intrethecal cytarabine ± Intrathecal High-dose cytarabine hydrocortisone Maintenance: methotrexete Maintenance: same + ± mercaptopurine periodic vincristine + Bone marrow transplant 3 prednisone Acute myeloid leukemia Induction: Cytarabine + either Cytarabine + mitoxantrone (AML) 9 daunbrublein or idarubieln High-dose cytarabine Post Induction: High-dose cytarabine ± other drugs such as etoposide Bone marrow transplant 3 Chronic lymophocytic Chlorambuell ± prednisone Claplatin, leukemia (CLL) Fludarabin cyclophosphamide, pentostatin, vinorlstine, doxorubicin Available in the USA only for mvestigational use. 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 mvestigational 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, radiotherapy or both. 6. The vitamin A analog lsotretmom (Accutane) can control pre-neoplastic lsions (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 thioguamme. The results of one large controlled trial in the United Kingdom suggest that mtensihbation 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 tretinom. 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 m chroni phase, 15% to 25% of patients with accelerated phase CML, and < 15% patients in blast crisis. Disease-free survival after bone marrow transplantation is adversely influenced by age > 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 m 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 allogemc bone marrow transplant. Chemotherapy alone is palliative. Radiolabeling of EC-MTX and EC-TDX with "'"Tc 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 mTc-EC-folate except EC-MTX and EC-TDX were used. Synthesis of p "Tc-EC-MTX and '"Tc-EC-TDX is shown in FIG. 2 and FIG. 3. Stability assay of p '"Tc-EC-folate, pp '"Tc-EC-MTX and 99 "Tc-EC-TDX Stability of p "Tc-EC-Folate, p "Tc-EC-MTX and p "Tc-EC-TDX was tested in serum samples. Briefly, 740 KBq of 1 mg "Tc-EC-Folate, "'" Tc-EC-MIX and pp '"Tc-EC-TDX was incubated in dog serum (200 μl) at 37 °C for 4 hours. The serum samples was diluted with 50% methanol in water and radio-TLC repeated at 0.5, 2 and 4 hours as described above. Tissue distribution studies Female Fischer 344 rats (150+25 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 6 cells/rat, a tumor cell line specific 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. In tissue distribution studies, each animal injected intravenously with 370-550 KBq of pp "Tc-EC-folate or p " ! Tc-EC (n=3/time point). The injected mass of each ligand was 10 μg per rat. At 20 min, 1, 2 and 4 h following administration of the radiopharmaceuticals, the anesthetized animals were sacrificed and the tumor and selected tissues were excised, weighed and counted for radioactivity by a gamma counter (Packard Instruments, Downers Grove, IL). The biodistribution of tracer in each sample was calculated as percentage of the injected dose per gram of tissue wet weight (%ID/g). Counts from a diluted sample of the original injectate were used for reference. Tumor/nontarget tissue count density ratios were calculated from the conesponding %ID/g values. Student-t test was used to assess the significance of differences between two groups. In a separate study, blocking studies were performed to determine receptor-mediated process. In blocking studies, for p "Tc-EC-folate was co-administrated (i.v.) with 50 and 150 μmol/kg folic acid to tumor bearing rats (n=3/group). Animals were killed 1 h post-injection and data was collected. Scintigraphic imaging and autoradiography studies Scintigraphic images, using a gamma camera (Siemens Medical Systems, Inc., Hoffman Estates, IL) equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hrs after i.v. injection of 18.5 MBq of p " ! Tc-labeled radiotracer. Whole-body autoradiogram were obtained by a quantitative image analyzer (Cyclone Storage Phosphor System, Packard, Meridian, CL). Following i.v. injection of 37 MBq of PP Tc-EC-folate, animal killed at 1 h and body was fixed in carboxymethyl cellulose (4%). The frozen body was mounted onto a cryostat (LKB 2250 cryomicrotome) and cut into 100 μm coronal sections. Each section was thawed and mounted on a slide. The slide was then placed in contact with multipurpose phosphor storage screen (MP, 7001480) and exposed for 15 h pp '"Tc- labeled). The phosphor screen was excited by a red laser and resulting blue light that is proportional with previously absorbed energy was recorded. RESULTS Chemistry and Stability of 99 "'Tc-EC-Folate 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. Radiosynthesis of EC-folate with '"Tc was achieved with high (>95%) radiochemical purity, 99m, Tc-EC-folate was found to be stable at 20 min. 1, 2 and 4 hours in dog serum samples. Biodistribution of pp '"Tc-EC-folate Biodistribution studies showed that tumor/blood count density ratios at 20 min-4 h gradually increased for Pw Tc-EC-folate, whereas these values decreased for pp "Tc-EC in the same time period (FIG. 4). %ID/g uptake values, tumor/blood and tumor/muscle ratios for pp "Tc-EC-folate and pp '"Tc-EC were given in Tables 3 and 4, respectively. TABLE 3 Biodistribution of 99m Tc-EC-folate in Breast Tumor-Bearing Rats % of injected yym Tc-EC-folate dose per organ or tissue 20 min l h 2 h 4 h Blood 0.370±0.049 0.165±0.028 0.086+0.005 0.058±0.002 Lung 0.294+0.017 0.164±0.024 0.092+0.002 0.063±0.003 Liver 0.274± 0.027 0.185+0.037 0.148+0.042 0.105 ±0.002 Stomach 0.130±0.002 0.557+0.389 0.118+0.093 0.073±0.065 Kidney 4.328+0.896 4.052+0.488 5.102+0.276 4.673±0.399 Thyroid 0.311+0.030 0.149±0.033 0.095+0.011 0.066±0.011 Muscle 0.058+0.004 0.0257±0.005 0.016+0.007 0.008±0.0005 Intestine 0.13 0.013 0.101±0.071 0.031 ±0.006 0.108±0.072 Urine 12.637+2.271 10.473±3.083 8.543+2.763 2.447±0.376 Tumor 0.298±0.033 0.147±0.026 0.106±0.029 0.071±0.006 Tumor Blood 0.812+0.098 0.894± 0.069 1.229+0.325 1.227+0.129 Tumor/Muscle 5.157+0.690 5.739+0.347 6.876+2.277 8.515+0.307 Values shown represent the mean ± standard deviation of data from 3 animals Scintigraphic Imaging and Autoradiography Studies Scintigraphic images obtained at different time points showed visualization of tumor in p Tc-EC-folate injected group. Contrary, there was no apparent tumor uptake in '"Tc-EC injected group (FIG. 6). Both radiotracer showed evident kidney uptake in all images. Autoradiograms performed at 1 h after injection of p '"Tc-EC-folate clearly demonstrated tumor activity. EXAMPLE 2 : TUMOR HYPOXIA TARGETING Synthesis of 2-(2-methyl-5-nitro- 1 H imidazolyl)ethylamine (amino analogue of metronidazole, MΝ- ΝH 2 ) Amino analogue of metronidazole 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-NH 2 . The structure was confirmed by 1H-NMR and mass spectroscopy (FAB-MS) m/z 171(M + H,100). Synthesis of Ethylenedicysteine-Metronidazole (EC- MN) Sodium hydroxide (2N, O.2 ml) was added to a stined 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. MΝ-NH: dihydrochloride salt (340 mg, 2.0 mmol) was then added. The mature was stined 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%). 1H-NMR (D 2 0) δ 2.93 (s, 6H, nitroimidazole-CH 3 ), 2.60- 2.95 (m, 4H and - CH 2 -SH of EC), 3.30-3.66 (m, 8H, ethylenediamine of EC and nitromidazole-CH 2 -CH 2 -NH 2 ), 3.70-3.99 (t, 2H, NH-CH-CO of EC), 5.05 (t, 4H, metronidazole-CH 2 -CH 2 -NH 2 ) (s, 2H, nitroimidazole C=CH). FAB MS m/z 572 (M + , 20). The synthetic scheme of EC-MN is shown in FIG. 7. Synthesis of 3-(2-nitro- 1H-imidazolyI)propylamine (amino analogue of nitroimidazole, NIM- NH 2 ) To a stined mixture containing 2-nitloimidazole (lg, 8.34 mmol) and Cs 2 ,CO 3 (2.9g, 8.90 mmol) in dimethylformaide (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. 108-111°C. 1H-NMR (CDC1 3 ) δ 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 MgSO 4 and evaporated to dryness to afford azido analogue (0.6 g, 75%>, TLC: hexane:ethyl acetate; 1 :1, Rf=0.42). 1H-NMR (CDC1 3 ) δ 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 MgSO 4 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. 1H-NMR (D 2 O) δ 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=2.1Hz),7.63 (d, IH, J=2.1Hz). Synthesis of ethylenedicysteine-nitroimidazole (EC- NIM) Sodium hydroxide (2N, 0.6 ml) was added to a stined 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-NH 2 hydrochloride salt (206.6 mg, 1.0 mmol) was then added. The mixture was stined 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. 8 A. The structure is confirmed by 1H-N R (D 2 O) (FIG. 8B). Radiolabeling of EC-MN and EC-ΝIM with 99m Tc Radiosynthesis of P Tc-EC-MN and pp "Tc-EC-NTM were achieved by adding required amount of pertechnetate into home-made kit containing the lyophilized residue of EC-MN or EC-NIM (3 mg), SnCl 2 , (100 μg), Na 2 HPO 4 (13.5 mg), ascorbic acid (0.5 mg) and NaEDTA (0.5 mg). Final pH of preparation was 7.4. Radiochemical purity was determined by TLC (ITLAC SG, German Sciences, Ann Arbor, MI) eluted with acetone (system A) and ammonium acetate (IM in water) methanol (4:1) (system B), respectively. From radio-TLC (Bioscan, Washington, DC) analysis, the radiochemical purity was >96% for both radiotracers. Synthesis of [ 1 l 8 β TF1]UFΛM/IΥISC/O-. a „„ndJ r [l"31 Tι]IMISO [Should this be ?] [ FI]uoride was produced by the cyclotron using proton inadiation of enriched 18 O-water in a small-volume silver target. The tosyl MISO (Hay et al, 1994) (20 mg) was dissolved in acetonitrile (1.5 ml), added to the kryptofix-fluoride complex. After heating, hydrolysis and column purification, A yield of 25-40% (decay conected) of pure product was isolated with the end of bombardment (EOB) at 60 min. HPLC was performed on a C-18 ODS- 20T column, 4.6 x 25 mm (Waters Corp., Milford, Mass), with water/acetonitrile, (80/20), using a flow rate of 1 ml/min. The no-carrier-added product conesponded to the retention time (6.12 min) of the unlabeled FMISO under similar conditions. The radiochemical purity was greater than 99%. Under the UV detector (310 nm), there were no other impurities. The specific activity of [ 18 F]FMISO determined was 1 Ci/μmol based upon UV and radioactivity detection of a sample of known mass and radioactivity. [ 13 I]IMISO was prepared using the same precursor (Cherif et al, 1994), briefly, 5 mg of tosyl MISO was dissolved in acetonitrile (1 ml), and Na 131 I (1 mCi in 0.1 ml IN NaOH) (Dupont New England Nuclear, Boston. MA) was added. After heating and purification, the product (60- 70% yield) was obtained. Radio-TLC indicated the Rf values of 0.01 for the final product using chloroform methanol (7:3) as an eluant. Stability assay of 99 '"Tc-EC-MN and 99 "'Tc-EC-NIM Stability of labeled PP Tc-EC-MN and p "Tc-EC-NIM were tested in serum samples. Briefly, 740 KBq of 1 mg " m Tc-EC- MN and Pm Tc-EC-NIM were incubated in dog serum (200 μl) at 37 °C for 4 hours. The serum samples were diluted with 50% methanol in water and radio-TLC repeated at 0.5, 2 and 4 hours as described above. Tissue distribution studies of ' P"P"/"nTn c-EC-MN Female Fischer 344 rats (150+25 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 6 cells/rat, a tumor cell line specific 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. In tissue distribution studies, each animal was injected intravenously with 370- 550 KBq of PPw Tc-EC-MN or p w Tc-EC (n=3/time point). The injected mass of pp "Tc-EC-MN was 10 μg per rat. At 0.5, 2 and 4 hrs following administration of the radiotracers, the rats were sacrificed and the selected tissues were excised, weighed and counted for radioactivity. The biodistribution of tracer in each sample was calculated as percentage of the injected dose per gram of tissue wet weight (%ID/g). Tumor/nontarget tissue count density radios were calculated from the conesponding %>ID/g values. The data was compared to [ 18 F]FMISO and [ 131 I]IMISO using the same animal model. Student t-test was used to assess the significance of differences between groups. Scintigraphic imaging and autoradiography studies Scintigraphic images, using a gamma camera (Siemens Medical Systems, Inc., Hoffman Estates, IL) equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hrs after i.v. injection of 18.5 MBq of each radiotracer. Whole-body autoradiogram was obtained by a quantitative image analyzer (Cyclone Storage Phosphor System, Packard, Meridian, CT). Following i.v. injection of 37 MBq of 9'"Tc-EC-MN, the animals were killed at 1 h and the body were fixed in carboxymethyl cellulose (4%) as previously described (Yang et al, 1995). The frozen body was mounted onto a cryostat (LKB 2250 cryomicrotome) and cut into 100 μm coronal sections. Each section was thawed and mounted on a slide. The slide was then placed in contact with multipurpose phosphor storage screen (MP, 7001480) and exposed for 15 hrs. To ascertain whether p "Tc-EC-NTM could monitor tumor response to chemotherapy, a group of rats with tumor volume 1.5 cm and ovarian tumor-bearing mice were treated with paclitaxel (40 mg/kg/rat, 80mg/kg/mouse, i.v.) at one single dose. The image was taken on day 4 after paclitaxel treatment. Percent of injected dose per gram of tumor weight with or without treatment was determined. Polarographic oxygen microelectrode pO 2 measurements To confirm tumor hypoxia, intratumoral pO 2 measurements were performed using the Eppendorf computerized histographic system. Twenty to twenty-five pO 2 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 pO 2 histogram between 0 and 100 mmHg with a class width of 2.5 mm. RESULTS Radiosynthesis and stability of 9P '"Tc-EC-MN and P9 '"Tc-EC-ΝIM Radiosynthesis of EC-MN and EC-NIM with pp '"Tc were achieved with high (>95%) radiochemical purity Radiochemical yield was 100%. P m Tc-EC-MΝ and pp '"Tc-EC-NIM (FIG. 13) were found to be stable at 0.5, 2 and 4 hrs in dog serum samples. There was no degradation products observed. Radiofluorination and radioiodination of MISO were achieved easily using the same precursor. In both labeled MISO analogues, the radiochemical purity was greater than 99%. In vivo tissue distribution studies The tissue distribution of • 99m Tc-EC-MN and 99m "Tc-EC in the tumor-bearing rats is shown in Tables 4 and 5. Due to high affinity for ionic 99m n Tc, there was no significant and consistent thyroid uptake, suggesting the in vivo stability of 99m Tc-EC-MN (Table 5). TABLE 4 Biodistribution of ■ 9 * 9 y m m Tc-EC in Breast Tumor-Bearing Rats % of injected 5 " π Tc-EC dose per orj gan or tissue 20min l h 2 h 4 h Blood 0.435+0.029 0.273±0.039 0.211±0.001 0.149±0.008 Lung 0.272±0.019 0.187±0.029 0.144+0.002 0.120+0.012 Liver 0.508±0.062 0.367+0.006 0.286±0.073 0.234+0.016 Stomach 0.136±0.060 0.127±0.106 0.037±0.027 0.043+0.014 Kidney 7.914±0.896 8.991±0.268 9.116±0.053 7.834± 1.018 Thyroid 0.219±0.036 0.229±0.118 0.106±0.003 0.083+0.005 Muscle 0.060±0.006 0.043±0.002 0.028±0.009 0.019+0.001 Intestine 0.173+0.029 0.787±0.106 0.401 ±0.093 0.103 ±0.009 Urine 9.124+0.808 11.045+6.158 13.192±4.505 8.693±2.981 Tumor 0.342±0.163 0.149±0.020 0.115±0.002 0.096+0.005 Tumor/Blood 0.776±0.322 0.544± 0.004 0.546±0.010 0.649+0.005 Tumor/Muscle 5.841±3.253 3.414±0.325 4.425± 1.397 5.093+0.223 Values shown represent the mean± standard deviation of data from 3 animals In blocking studies, tumor/muscle and tumor/blood count density ratios were significantly decreased (p<0.01) with folic acid co-administrations (FIG. 5). TABLE 5 Biodistribution of 99m Tc-EC-metronidazole conjugate in breast tumor bearing rats 1 30 Min. 2 Hour 4 Hour Blood 1.46±0.73 1.19+0.34 0.76±0.14 Lung 0.79±0.39 0.73 + 0.02 0.52+0.07 Liver 0.83±0.36 0.91 +0.11 0.87±0.09 Spleen 0.37+0.17 0.41±0.04 0.37±0.07 Kidney 4.30± 1.07 5.84±0.43 6.39+0.48 Muscle 0.08±0.03 0.09±0.01 0.07±0.01 Intestine 0.27±0.12 0.39±0.24 0.22±0.05 Thyroid 0.051±0.16 0.51+0.09 0.41±0.02 Tumor 0.034+0.13 0.49±0.02 0.50±0.09 1. Each rat received 99m Tc-EC-metronidazole (10 μCi, iv). Each value is percent of injected dose per gram weight (n=3)/time interval. Each data represents mean of three measurements with standard deviation. Biodistribudon studies showed that tumor/blood and tumor/muscle count density ratios at 0.54 hr gradually increased for p "Tc-EC-MN, [ 18 F]FMISO and [ 131 I]IMISO, whereas these values did not alter for p "Tc-EC in the same time period (FIG. 9 and FIG. 10). [ 18 F]FMISO showed the highest tumor-to-blood uptake ratio than those with [ 131 I]IMISO and p "Tc-EC-MN at 30 min, 2 and 4 hrs post-injection. Tumor/blood and tumor/muscle ratios for p "Tc-EC-MΝ and [ 131 I]IMISO at 2 and 4 hrs postinjection were not significantly different (p<0.05). Scintigraphic imaging and autoradiographic studies Scintigraphic images obtained at different time points showed visualization of tumor in p "Tc-EC-MN and p Tc-EC-NIM groups. Contrary, there was no apparent tumor uptake in PPm Tc-EC injected group (FIG. 11). Autoradiograms performed at 1 hr after injection of p "Tc-EC-MΝ clearly demonstrated tumor activity (FIG. 12). Compare to m Tc-EC-NM, P m Tc-EC-NIM appeared to provide better scintigraphic images due to higher tumor-to-background ratios. In breast tumor-bearing rats, tumor uptake was markedly higher in PP Tc-EC-NHVI group compared to P w Tc-EC (FIG. 14A). Data obtained from percent of injected dose of P m Tc-EC-NIM per gram of tumor Weight indicated that a 25% decreased uptake in the rats treated with paclitaxel when compared to control group (FIG. 14B). In ovarian tumor-bearing mice, there was a decreased tumor uptake in mice treated with paclitaxel (FIG. 15A and FIG. 15B). Similar results were observed in sarcoma-bearing (FIG. 15C and FIG. 15D). Thus, p "Tc-EC-NIM could be used to assess tumor response to paclitaxel treatment. Polarographic oxygen microelectrode pO 2 measurements Intratumoral PO 2 measurements of tumors indicated the tumor oxygen tension ranged 4.6+1.4 mmHg 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 stined 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 stined 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. 16. Stability Assay of 99 "'Tc-EC-GAP Radiolabeling of EC-GAP with P m Tc was achieved using the same procedure described previously. The radiochemical purity was 100%. Stability of labeled p "Tc-EC-GAP was tested in serum samples. Briefly, 740 KBq of 1 mg P Tc-EC-GAP was incubated in dog serum (200 μl) at 37 °C for 4 hours. The serum samples were diluted with 50% methanol in water and radio-TLC repeated at 0.5, 2 and 4 hours as described above. Scintigraphic Imaging Studies Scintigraphic images, using a gamma camera equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hrs after i.v. injection of 18.5 MBq of each radiotracer. RESULTS Stability Assay of "'"Tc-EC-GAP P w Tc-EC-GAP found to be stable at 0.5, 2 and 4 hrs in dog serum samples. There was no degradation products observed. Scintigraphic imaging studies Scintigraphic images obtained at different time points showed visualization of tumor in PP Tc-EC-GAP group. The optimum uptake is at 30min to 1 hour post-administration (FIG. 17). EXAMPLE 4: IMAGING TUMOR APOPTOTIC CELLS Synthesis of Ethylenedicysteine- Annexin V (EC-ANNEX) Sodium bicarbonate (IN, 1 ml) was added to a stined 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 stined 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. Stability Assay of 99 "Tc-EC-AΝΝEX Radiolabeling of EC-ANNEX with "Tc was achieved using the same procedure described in EC-GAP. The radiochemical purity was 100%. Stability of labeled P Pm Tc-EC-ANNEX was tested in serum samples. Briefly, 740 KBq of 1 mg ppm Tc-EC-ANNEX was incubated in dog serum (200 μl) at 37 °C for 4 hours. The serum samples were diluted with 50% methanol in water and radio-TLC repeated at 0.5, 2 and 4 hours as described above. Scintigraphic Imaging Studies Scintigraphic images, using a gamma camera equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hrs after i.v. injection of 18.5 MBq of the radiotracer. The animal models used were breast, ovarian and sarcoma. Both breast and ovarian-tumor bearing rats are known to overexpress high apoptotic cells. The imaging studies were conducted on day 14 after tumor cell inoculation. To ascertain the tumor treatment response, the pre-imaged mice were administered paclitaxel (80 mg Kg, iv, day 14) and the images were taken on day 18. RESULTS Stability Assay of 9P '"Tc-EC-ANNEX PP Tc-EC-ANNEX found to be stable at 0.5, 2 and 4 hrs in dog serum samples. There was no degradation products observed. Scintigraphic imaging studies Scintigraphic images obtained at different time points showed visualization of tumor in Tc-EC-ANNEX group (FIGs. 18-20). The images indicated that highly apoptotic cells have more uptake of P m Tc-EC- ANNEX. There was no marked difference of tumor uptake between pre- and post-[aclitaxel treatment in the high apoptosis (ovarian tumor-bearing) group (FIG. 19 A and FIG. 19B) and in the low apoptosis (sarcoma tumor-bearing) group (FIG. 20A and FIG. 20B). EXAMPLE S: IMAGING TUMOR ANGIOGENESIS Synthesis of (Amino Analogue of Colchcine, COL-NH 2 ) Demethylated amino and hydroxy analogue of colchcine was synthesized according to the previously described methods (On 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-NH 2 . The structure was confirmed by 1H-NMR and mass spectroscopy (FAB-MS). 1H-NMR (CDCl 3 )δ 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 Ethylenedicysteine-Colchcine (EC-COL) Sodium hydroxide (2N, 0.2 ml) was added to a stined solution of EC (134 mg, 0.50 mmol) in water (5 ml). To this colotiess solution, sulfo-NHS (217 mg, 1.0 mmol) and EDC (192 mg, 1.0 mmol) were added. COL-NH 2 (340 mg, 2.0 mmol) was then added. The mixture was stined 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%). 1H-NMR (D 2 O) δ 7.39 (S, IH), 7.20 (d, IH, J=12Hz), 7.03 (d, IH, J=12Hz), 6.78 (S,1H), 4.25-4.40 (m, IH), 3.87 (S, 3H, -OCH 3 ), 3.84 (S, 3H, -OCH 3 ), 3.53 (S, 3H, -OCH 3 ), 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. 21. Radiolabeling of EC-COL and EC with pp, "Tc Radiosynthesis of Tc-EC-COL was achieved by adding required amount of '"Tc-pertechnetate into home-made kit containing the lyophilized residue of EC-COL (5 mg), SnCl 2 (100 μg), Na 2 HPO 4 (13.5 mg), ascorbic acid (0.5 mg) and NaEDTA (0.5 mg). Final pH of preparation was 7.4. p '"Tc-EC was also obtained by using home-made kit containing the lyophilized residue of EC (5 mg), SnCi 2 (100 μg), Na HPO 4 (13.5 mg), ascorbic acid (0.5 mg) and NaEDTA (0.5 mg) at pH 10. Final pH of preparation was then adjusted to 7.4. Radiochemical purity was determined by TLC (ITLC SG, Ge man Sciences, Ann Arbor, MI) eluted with ammonium acetate (IM in water) methanol (4:1). Radio-thin layer chromatography (TLC, Bioscan, Washington, DC) was used to analyze the radiochemical purity for both radiotracers. Stability Assay of 9P '"Tc-EC-COL Stability of labeled pp "Tc-EC-COL was tested in serum samples. Briefly, 740 KBq of 5 mg pp "Tc-EC-COL was incubated in the rabbinate serum (500 μl) at 37 °C for 4 hours. The serum samples was diluted with 50% methanol in water and radio-TLC repeated at 0.5, 2 and 4 hours as described above. Tissue Distribution Studies Female Fischer 344 rats (150+25 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 specific 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. In tissue distribution studies, each animal was injected intravenously with 370-550 KBq of pp "Tc-EC-COL or "Tc-EC (n=3/time point). The injected mass of "Tc-EC-COL was 10 μg per rat. At 0.5, 2 and 4 hrs following administration of the radiotracers, the rats were sacrificed and the selected tissues were excised, weighed and counted for radioactivity. The biodistribution of tracer in each sample was calculated as percentage of the injected dose per gram of tissue wet weight (%ID/g). Tumor/nontarget tissue count density ratios were calculated from the conesponding %ID/g values. Student t-test was used to assess the significance of differences between groups. Scintigraphic Imaging Studies Scintigraphic images, using a gamma camera (Siemens Medical Systems, Inc., Hoffman Estates, IL) equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hrs after i.v. injection of 300 μCi of PP Tc-EC-COL and pp '"Tc-EC. Computer outlined region of interest (ROI) was used to quantitate (counts per pixel) the tumor uptake versus normal muscle uptake. RESULTS Radiosynthesis and stability of 99 "'Tc-EC-COL Radiosynthesis of EC-COL with P Tc was achieved with high (>95%) radiochemical purity (FIG. 21). "Tc-EC-COL was found to be stable at 0.5, 2 and 4 hrs in rabbit serum samples. There was no degradation products observed (FIG. 22). In Vivo Biodistribution In vivo biodistribution of m Tc-EC-COL and PPm Tc-EC in breast-tumor-bearing rats are shown in Tables 4 and 6. Tumor uptake value (%ID/g) of 9 " ! Tc-EC~COL at 0.5, 2 and 4 hours was 0.436+0.089, 0.395+0.154 and 0.221+0.006 (Table 6), whereas those for p "Tc-EC were 0.342±0.163, 0.115±0.002 and 0.097±0.005, respectively (Table 4). Increased tumor-to-blood (0.52±0.12 to 0.72±0.07) and tumor-to-muscle (3.47 ± 0.40 to 7.97 + 0.93) ratios as a function of time were observed in p '"Tc-EC-COL group (FIG. 23). Conversely, tumor-to-blood and tumor-to-muscle values showed time-dependent decrease with p "Tc-EC when compared to pp '"Tc-EC-COL group in the same time period (FIG. 24). TABLE 6 Biodistribution of 99m Tc-EC-Colchicine in Breast Tumor Bearing Rats 30 Min. 2 Hour 4 Hour Blood 0.837 ± 0.072 0.606 + 0.266 0.307 ± 0.022 Lung 0.636 ± 0.056 0.407 ± 0.151 0.194 ± 0.009 Liver 1.159 ± 0.095 1.051 ± 0.213 0.808 + 0.084 Spleen 0.524 ± 0.086 0.559 ± 0.143 0.358 ± 0.032 Kidney 9.705 ± 0.608 14.065 ± 4.007 11.097 ± 0.108 Muscle 0.129 ± 0.040 0.071 ± 0.032 0.028 ± 0.004 Stomach 0.484 ± 0.386 0.342 ± 0.150 0.171 + 0.123 Uterus 0.502 + 0.326 0.343 + 0.370 0.133 ± 0.014 Thyroid 3.907 ± 0.997 2.297 ± 0.711 1.709 + 0.776 Tumor 0.436 ± 0.089 0.395 ± 0.154 0.221 ± 0.006 * Each rat received 99m Tc-EC-Colchicine (10 μCi, iv.). Each value is the percent of injected dose per gram tissue weight (n=3)/time interval. Each data represents mean of three measurements with standard deviation. TABLE 7 Rf Values Determined by Radio-TLC (ITLC-SG) Studies System A* System Bf y ym Tc-EC-folate 0 1(>95%) 99m Tc-EC- 0 1(>95%) Free 99m Tc 1 1 Reduced 99m Tc 0 0 * Acetone f Ammonium Acetate (IM in water) Methanol (4:1) Gamma Scintigraphic Imaging of 9P '"Tc-EC-COL in Breast Tumor-Bearing Rats In vivo imaging studies in three breast-tumor-bearing rats at 1 hour post-administration indicated that the tumor could be visualized well with pp Tc-EC-COL group (FIG. 25), whereas, less tumor uptake in the pp '"Tc-EC group was observed (FIG. 26). Computer outlined region of interest (ROI) showed that tumor/background ratios in p "Tc-EC-COL group were significantly higher than 9 " c-EC group (FIG. 27). TUMOR GLYCOLYSIS TARGETING EXAMPLE 6: DEVELOPMENT OF 99m Tc-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-τhiazolidine-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 ^-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 stined 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 stined 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. 36. The structure is confirmed by ^-NMR (FIGS. 38A-B), mass spectrometry (FIGS. 39A-B) and elemental analysis (Galbraith Laboratories, Inc. Knoxville, TN). Elemental analysis C 39 H 75 N 10 S 4 Oι 9 .15H 2 O (C,H,N,S), Calc. C:33.77, H:7.58, Ν:10.11, S:9.23; found C:32.44, H:5.90, Ν: 10.47, S:10.58. UV wavelength of EC-neomycin was shifted to 270.5 nm when compared to EC and neomycin (FIGS. 40A-C) Radiolabeling of EC-MN and EC-neomycin with 99m Tc Radiosynthesis of 99m Tc-EC and 99m Tc-EC-neomycin were achieved by adding required amount of 99m Tc-pertechnetate into home-made kit containing the lyophilized residue of EC or EC-neomycin (10 mg), SnCl 2 (100 μg), Na 2 HPO 4 (13.5 mg) and ascorbic acid (0.5 mg). NaEDTA (0.5 mg) in 0.1 ml of water was then added. Final pH of preparation was 7.4. Radiochemical purity was determined by TLC (ITLC SG, Ge man Sciences, Ann Arbor, MI) eluted with ammonium acetate (IM in water) :methanol (4:1). From radio-TLC (Bioscan, Washington, DC) analysis (FIG. 41) and HPLC analysis (FIGS. 42-45), the radiochemical purity was >95% for both radiotracers. Stability assay of 99m Tc-EC and 99m Tc-EC-neomycin Stability of labeled Tc-EC and Tc-EC-neomycin were tested in dog serum samples. Briefly, 740 KBq of 1 mg 99m Tc-EC and 99m Tc-EC-neomycin were incubated in dog serum (200 μl) at 37°C for 4 hours. The serum samples were diluted with 50%) methanol in water and radio- TLC repeated at 0.5, 2 and 4 hours as described above. Tissue distribution studies of 99 Tc-EC-neomycin Female Fischer 344 rats (150+25 g) (Harlan Sprague-Dawley, Indianapolis, IN) were innoculated subcutaneously with 0.1 ml of mammary tumor cells from the 13762 tumor cell line suspension (10 6 cells/rat, a tumor cell line specific 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. In tissue distribution studies, each animal was injected intravenously with 10-20 μCi of 99m Tc-EC or 99m Tc-EC-neomycin (n=3/time point) . The inj ected mass of 99m Tc-EC-neomycin was 200 μg per rat. At 0.5, 2 and 4 hours following administration of the radiotracers, the rats were sacrificed and the selected tissues were excised, weighed and counted for radioactivity. The biodistribution of tracer in each sample was calculated as percentage of the injected dose per gram of tissue wet weight (%ID/g). Tumor/nontarget tissue count density ratios were calculated from the conesponding %>ID/g values. When compared to 99m Tc-EC (Table 4) and free technetium (Table 9), tumor-to tissue ratios increased as a function of time in 9m Tc-EC- neomycin group (Table 8). Scintigraphic imaging studies Scintigraphic images, using a gamma camera (Siemens Medical Systems, Inc., Hoffman Estates, IL) equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hours after i.v. injection of 100 μCi of each radiotracer. Compare to 99m Tc-EC, high uptake in the tumors was observed (FIG. 37A). Preliminary clinical imaging studies were conducted in a patient with breast cancer. The tumor was visualized well at 2 hours post-administration of 99m T: c-EC-neomycin (FIG. 37B). TABLE 8 Biodistribution of 99m Tc-EC-neomycin in Breast Tumor Bearing Rats 30 Min. l Hour 2 Hour 4 Hour Blood 0.463±0.007 0.262+0.040 0.139+0.016 0.085±0.004 Lung 0.344±0.011 0.202+0.030 0.114±0.014 0.080±0.003 Liver 0.337±0.012 0.269+0.013 0.221 ±0.020 0.195+0.012 Stomach 0.279+0.039 0.147+0.001 0.061+0.008 0.054+0.008 Spleen 0.159+0.008 0.114+0.013 0.095+0.007 0.089+0.003 Kidney 8.391±0.395 8.804+0.817 8.356±0.408 8.638+0.251 Thyroid 0.349±0.008 0.202+0.028 0.114±0.007 0.086±0.001 Muscle 0.093±0.001 0.049+0.010 0.021 ±0.006 O.OIO±O.OOI Intestine 0.159±0.004 0.093+0.014 0.061 ±0.004 0.266±0.200 Urine 25.402± 8.621 21.786+2.690 0.224+0.000 2.609+2.377 Tumor 0.419+0.023 0.279+0.042 0.166+0.023 0.131+0.002 Brain 0.022+0.001 0.014+0.003 0.010+0.001 0.007+0.001 Heart 0.147+0.009 0.081+0.012 0.040+0.004 0.029+0.002 Tumor/Blood 0.906+0.039 1.070+0.028 1.196+0.061 1.536+0.029 Tumor/Muscle 4.512+0.220 5.855+0.458 8.364+1.469 12.706+0.783 Tumor/Brain 19.495+1.823 20.001+0.890 17.515+2.035 20.255+1.693 Values shown represent the mean ± standard deviation of data from 3 animals. TABLE 9 Biodistribution of • 99m, Tc Pertechnetate in Breast Tumor Bearing Rats 30 Min. 2 Hour 4 Hour Blood 1.218+0.328 0.666±0.066 0.715±0.052 Lung 0.646+0.291 0.632+0.026 0.387±0.024 Liver 0.541±0.232 0.304±0.026 0.501±0.081 Spleen 0.331+0.108 0.187+0.014 0.225+0.017 Kidney 0.638+0.197 0.489±0.000 0.932±0.029 Thyroid 24.821 + 5.181 11.907±15.412 17.232±5.002 Muscle 0.130±0.079 0.076± 0.002 0.063+0.003 Intestine 0.153±0.068 0.186±0.007 0.344±0.027 Tumor 0.591 + 0.268 0.328+0.016 0.423±0.091 Brain 0.038+0.014 0.022+0.002 0.031+0.009 Heart 0.275+0.089 0.145+0.015 0.166+0.012 Tumor Blood 0.472+0.093 0.497+0.073 0.597+0.144 Tumor/Muscle 4.788+0.833 4.302+0.093 6.689+1.458 Tumor/Liver 1.084+0.023 1.084+0.115 0.865+0.270 Values shown represent the mean ± standard deviation of data from 3 animals. In vitro cellular uptake of • 99m η Tc-EC-drug conjugates To evaluate the cellular uptake of 99m Tc-EC-drug conjugates, each well containing 80,000 cells (A549 lung cancer cell line) was added with 2 μCi of 99m Tc-EC -neomycin and 18 F-FDG. After incubation at 0.5-4 hours, the cells were washed with phosphate buffered saline 3 times and followed by trypsin to lose the cells. The cells were then counted by a gamma counter. 99m Tc-EC-neomycin showed highest uptake among those agents tested in human lung cancer cell line (FIG. 46). Effect of glucose on cellular uptake of 99m Tc-EC-neomycin and 18 F-FDG Neomycin is known to influence glucose absorption (Rogers et al., 1968; Fanciulli et al., 1994). Previous experiments have shown that Tc-EC-neomycin has higher uptake than F- FDG in human lung cancer cell line (A549). To determine if uptake of 99m Tc-EC-neomycin is mediated via glucose-related mechanism, glucose (0.1 mg-2.0 mg) was added to each well containing either 50,000 (breast) cells or 80,000 cells (lung) along with 2 μCi of 99m Tc-EC- neomycin and F-FDG. After incubation, the cells were washed with phosphate buffered saline 3 times and followed by trypsin to lose the cells. The cells were then counted by a gamma counter. By adding glucose at the concentration of 0.1-2.0 mg/well, decreased uptake of 99m Tc- EC-neomycin in two lung cancer cell lines and one breast cell line was observed. Similar results were observed in ] 8 F-FDG groups. 99m Tc-EC (control) showed no uptake. The findings suggest that the cellular uptake of 99m Tc-EC-neomycin may be mediated via glucose-related mechanism (FIGS. 47, 48A and 48B). EXAMPLE 7: TUMOR METABOLIC IMAGING WITH 99m Tc-EC-DEOXYGLUCOSE Synthesis of EC-deoxyglucose (EC-DG) Sodium hydroxide (IN, 1ml) was added to a stined 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 stined 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 in the salt form weighed 568.8 mg. The synthetic scheme is shown in Figure 59. The structure was confirmed by mass spectrometry (FIG. 60) and proton NMR (FIGS. 61 and 62). Radiochemical purity of 99m Tc-EC-DG was 100% as determined by radio-TLC (FIG. 63) and HPLC (FIGS. 64 and 65) analysis. 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 (FIGS. 66-68). In vitro cellular uptake assay In vitro cellular uptake assay was conducted by using a human lung cancer cell line (A549). Two μCi of 99m Tc-EC-DG and 18 F-FDG were added to wells containing 80,000 cells each. After incubation at 0.5-4 hours, the cells were washed with phosphate buffered saline 3 times and followed by trypsin to lose the cells. The cells were then counted by a gamma counter. The uptake of 99m Tc-EC-DG was comparable to FDG (FIG. 69). Effect of d- and 1-glucose on cellular uptake of 99m Tc-EC-deoxyglucose and 18 F-FDG To evaluate if the uptake of 99m Tc-EC-deoxyglucose is mediated via d-glucose mechanism, d- and 1-glucose (1 mg and 2.0 mg) were added to , each well containing either breast or lung cancer cells (50,000/0.5 ml/well), along with 2μCi of 99m Tc-EC-deoxyglucose and F-FDG. After 2 hours incubation, the cells were washed with phosphate buffered saline 3 times and followed by trypsin to lose the cells. The cells were counted by a gamma counter. By adding glucose at the concentration of 1-2.0 mg/well, a decreased uptake of ""Tc- EC-deoxyglucose and 18 F-FDG by d-glucose in breast and lung cancer cells was observed. However, there was no influence on both agents by 1-glucose (FIG. 70-73). The findings suggest that the cellular uptake of 99m Tc-EC-deoxyglucose is mediated via d-glucose mechanism. Effect of EC-deoxyglucose loading on blood glucose level in normal rats Previous experiments have shown that cellular uptake of 99m Tc-EC-deoxyglucose is similar to FDG. For instance, the hexokinase assay (glucose phosphorylation) was positive. The uptake of 99m Tc-EC-deoxyglucose is mediated via d-glucose mechanism. This study is to determine whether blood glucose level could be induced by either FDG or EC-deoxyglucose and suppressed by insulin. Normal healthy Fischer 344 rats (weight 145-155 g) were fasting overnight prior to the experiments. The concentration of glucosamine hydrochloride, FDG and EC-deoxyglucose prepared was 60% and 164% (mg/ml). The blood glucose level (mg/dl) was determined by a glucose meter (Glucometer DEX, Bayer Coφoration, Elkhart, IN). Prior to the study, the baseline of blood glucose level was obtained. Each rat (n=3 /group) was administered 1.2 mmol/kg of glucosamine, FDG and EC-deoxyglucose. In a separate experiment, a group of rats was administered EC-deoxyglucose and FDG. Insulin (5 units) was administered after 30 minutes. Blood samples were collected from the tail vein every 30 minutes up to 6 hours post- administration. Blood glucose level was induced by bolus intravenous administration of glucosamine, FDG and EC-deoxyglucose. This increased blood glucose level could be suppressed by co- administration of EC-deoxyglucose or FDG and insulin (FIGS. 74 and 75). Tissue distribution studies of 99m Tc-EC-DG For breast tumor-bearing animal model, female Fischer 344 rats (150+25 g) (Harlan Sprague-Dawley, Indianapolis, IN) were innoculated subcutaneously with 0.1 ml of mammary tumor cells from the 13762 tumor cell line suspension (10 6 cells/rat, a tumor cell line specific to Fischer rats) into the hind legs using 25-gauge needles. Studies were performed 14 to 17 days after implantation when rumors reached approximately 1 cm diameter. Rats were anesthetized with ketamine (10-15 mg/rat, intraperitoneally) before each procedure. For lung tumor-bearing animal model, each athymic nude mouse (20-25g) was innoculated subcutaneously with 0.1 ml of human lung tumor cells from the A549 tumor cell line suspension (10 6 cells/mouse) into the hind legs using 25-gauge needles. Studies were performed 17 to 21 days after implantation when tumors reached approximately 0.6 cm diameter. In tissue distribution studies, each animal was injected intravenously with 10-20 μCi (per rat) or 1-2 μCi (per mouse) of 99m Tc-EC or 99m Tc-EC-DG (n=3/time point). The injected mass of 99m Tc-EC-DG was 1 mg per rat. At 0.5, 2 and 4 hours following administration of the radiotracers, the rodents were sacrificed and the selected tissues were excised, weighed and counted for radioactivity. The biodistribution of tracer in each sample was calculated as percentage of the injected dose per gram of tissue wet weight (%ID/g). Tumor/nontarget tissue count density ratios were calculated from the conesponding %ID/g values. When compared to 99m Tc-EC (Table 4) and free technetium (Table 9), tumor-to tissue ratios increased as a function of time in 99ra Tc-EC-DG group (FIGS. 76-80). Scintigraphic Imaging Studies Scintigraphic images, using a gamma camera equipped with low-energy, parallel-hole collimator, were obtained 0.5, 2 and 4 hours after i.v. injection of 100 μCi of the radiotracer. The animal model used was breast tumor-bearing rats. Tumor could be visualized well when compared to 99m Tc-EC (control group) (FIG. 81). Preliminary clinical studies were conducted in 5 patients (3 brain tumors and 2 lung diseases). The images were obtained at 1-2 hours post- administration. 99m Tc-EC-DG was able to differentiate benign versus malignant tumors. For instance, malignant astrocytoma showed high uptake (FIGS. 82A, 82B, 83 A and 83B). Benign meningioma showed poor uptake compared to malignant meningioma (Figs 84A and B). Poor uptake was observed in patient with TB (FIG. 85 A and FIG. 85B), but high uptake was observed in lung tumor (FIG. 86A, FIG. 86B, and FIG. 86C). 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 mvention have been described in terms of prefened 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. 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Claims: CLAIMS 1. A composition for imaging comprising: a) a radionuclide label; b) ethylenedicysteine; and c) a tissue specific ligand conjugated to said ethylenedicysteine; wherein said ethylenedicysteine forms an N 2 S 2 chelate with said radionuclide label. 2. The composition of claim 1 , wherein said tissue specific ligand may be conjugated to said ethylenedicysteine on one or both acid arms of the ethylenedicysteine. 3. The composition of claim 1, wherein said radionuclide is p "Tc, 188 Re, 186 Re, 183 Sm, 1 66 Ho, 90 Y, 89 Sr, 67 Ga, 68 Ga, m In, 183 Gd, 59 Fe, 225 Ac, 212 Bi, 211 At, 64 Cu or 62 Cu. 4. The composition of claim 3, wherein said radionuclide is p '"Tc. 5. The composition of claim 1, wherein said tissue specific ligand is an anticancer agent, DNA topoisomerase inhibitor, antimetabohte, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, nucleotide, organ specific ligand, antibiotic, antifungal, antibody, glutamate pentapeptide or an agent that mimics glucose. 6. The composition of claim 5, wherein said tissue specific ligand is an anticancer agent. 7. The composition of claim 6, wherein said anticancer agent may be selected from the group consisting of methotrexate, doxorubicin, tamoxifen, paclitaxel, topotecan, LHRH, mitomycin C, etoposide tomudex, podophyllotoxin, mitoxantrone, camptothecin, colchicine, endostatin, fludarabin, gemcitabine and tomudex. 8. The composition of claim 5, wherein said tissue specific ligand is a tumor marker. The composition of claim 8, wherein said tumor marker is PSA, ER, PR, CA-125, CA- 199, CEA AFP, interferons, BRCA1, HER-2/neu, cytoxan, p53, endostatin or a monoclonal antibody (e.g., antisense). 10. The composition of claim 5, wherein the tissue specific ligand is a folate receptor targeting ligand. 11. The composition of claim 10, wherein the folate receptor targeting ligand is folate, methotrexate or tomudex. 12. The composition of claim 11, further defined as pp "Tc-EC-folate. 13. The composition of claim 11 , further defined as P m Tc-EC-methotrexate. 14. The composition of claim 11, further defined as pp '"Tc-EC-tomudex. 15. The composition of claim 5, wherein the tissue specific ligand is a tumor apoptotic cell targeting ligand or a tumor hypoxia targeting ligand. 16. The composition of claim 15, wherein the tissue specific ligand is annexin V, colchicine, nitroimidazole, mitomycin or metronidazole. 17. The composition of claim 16, further defined as pp "Tc-EC-annexin V. 18. The composition of claim 16, further defined as p '"Tc-EC-colchicine. 19. The composition of claim 16, further defined as PPw Tc-EC-nitroimidazole. 20. The composition of claim 16, further defined as 99m TC-EC-metronidas. 21. The composition of claim 5, wherein the tissue specific ligand is glutamate pentapeptide (molecular weight 750-15,000). 22. The composition of claim 21, further defined as 99mTc-EC-glutamate pentapeptide. 23. The composition of claim 5, wherein the tissue specific ligand is an agent that mimics glucose. 24. The composition of claim 23, wherein the agent that mimics glucose is neomycin, kanamycin, getnamycin, paromycin, amikacin, tobramycin, netilmicin, ribostamycin, sisomicin, micromicin, lividomycin, dibekacin, isepamicin, astromicin, or an aminoglycoside. 25. The composition of claim 24, further defined as 99mTc-EC-neomycin. 26. The composition of claim 24, further defined as 99mTc-EC-kanamycin. 27. The composition of claim 24, further defined as 99mTc-EC-aminoglycosides. 28. The composition of claim 24, further defined as 99mTc-EC-gentamycin. 29. The composition of claim 24, further defined as 99mTc-EC-tobranιycin. 30. The composition of claim 2, further comprising a linker conjugating EC to said tissue specific ligand. 31. The composition of claim 30, wherein the linker is a water soluble peptide, glutamic acid, aspartic acid, bromo ethylacetate, ethylene diamine or lysine. 32. The composition of claim 31, wherein the tissue specific ligand is estradiol, topotecan, paclitaxel, raloxifen, etoposide, doxorubricin, mitomycin C, endostatin, annexin V, LHRH, octreotide, VIP, methotrexate or folic acid. 33. A method of synthesizing a radiolabeled ethylenedicysteine derivative for imaging comprising the steps: a) obtaining a tissue specific ligand; b) admixing said ligand with ethylenedicysteine (EC) to obtain an EC-tissue specific ligand derivative; and c) admixing said EC-tissue specific ligand derivative with a radionuclide and a reducing agent to obtain a radionuclide labeled EC-tissue specific ligand derivative, wherein the EC forms an N 2 S 2 chelate with the radionuclide. 34. The method of claim 33, wherein said reducing agent is a dithionite ion, a stannous ion or a fenous ion. 35. A method for labeling a tissue specific ligand for imaging, comprising the steps: a) obtaining a tissue specific ligand; b) admixing the tissue specific ligand with ethylenedicysteine (EC) to obtain an EC- ligand drug conjugate; and c) reacting the drug conjugate with "Tc in the presence of a reducing agent to form an N 2 S 2 chelate between the ethylenedicysteine (with or without linker) and the pm Tc. 36. The method of claim 35, wherein the tissue specific ligand is an anticancer agent, DNA topoisomerase inhibitor, antimetabohte, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, organ specific ligand, antibiotic, antifungal, glutamate pentapeptide or an agent that mimics glucose. 37. The method of claim 36, wherein the reducing agent is a dithionite ion, a stannous ion or a fenous ion. 38. A method of imaging a site within a mammalian body comprising the steps of administering an effective diagnostic amount of a composition comprising a 99mTc labeled ethylenedicysteine-tissue specific ligand conjugate and detecting a radioactive signal from the 99m Tc localized at the site. 39. The method of claim 38, wherein the site is a tumor. 40. The method of claim 38, wherein the site is an infection. 41. The method of claim 38, wherein the site is breast cancer, ovarian cancer, prostate cancer, endometrium, heart, lung, brain, liver, folate (+) cancer, ER (+) cancer, spleen, pancreas, or intestine. 42. A kit for preparing a radiopharmaceutical preparation, said kit comprising a sealed container including a predetermined quantity of an ethylenedicysteine-tissue specific ligand conjugate composition and a sufficient amount of reducing agent to label the conjugate with "Tc. 43. The kit of claim 42, wherein the ethylenedicysteine-tissue specific ligand conjugate composition further comprises a linker between the ethylenedicysteine and the tissue specific ligand. 44. The kit of claim 42, wherein the tissue specific ligand is an anticancer agent, DNA topoisomerase inhibitor, antimetabohte, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, organ ligand, antibiotic, antifungal, glutamate pentapeptide or an agent that mimics glucose. 45. The kit of claim 43, wherein the tissue specific ligand is estradiol, topotecan, paclitaxel, raloxifen, etoposide, doxorubricin, mitomycin C, endostatin, annexin V, LHRH, octreotide, VIP, methotrexate or folic acid. 46. The kit of claim 45, wherem the linker is a water soluble peptide, glutamic acid, polyglutamic acid, aspartic acid, polyaspartic acid, bromoethylacetate, ethylenediamine or lysine. 47. A reagent for preparing a scintigraphic imaging agent comprising a tissue specific ligand covalently linked to a P Tc binding moiety. 48. The reagent of claim 47, wherein the pp '"Tc binding moiety is ethylenedicysteine. 49. The reagent of claim 48, wherein the tissue specific ligand is an anticancer agent, DNA topoisomerase inhibitor, antimetabohte, tumor marker, folate receptor targeting ligand, tumor apoptotic cell targeting ligand, tumor hypoxia targeting ligand, DNA intercalator, receptor marker, peptide, organ specific ligand, antibiotic, antifungal, glutamate pentapeptide or an agent that mimics glucose. 50. The reagent of claim 48, further comprising a linker between said tissue specific ligand and said 9p "Tc binding moiety. 51. A method of determining effectiveness of a candidate drug on a tumor, said method comprising: a) obtaining a candidate drug; b) conjugating said candidate drug with ethylenedicysteine (EC) to produce an EC- candidate drug conjugate; c) chelating said candidate drag conjugate with P m Tc to produce a pp '"Tc-EC- candidate drug conjugate; d) introducing said p '"Tc-EC-candidate drug conjugate into a patient with a tumor; and e) imaging said patient to determine the effectiveness of the candidate drug against the tumor.

Inventors: KIM E EDMUND, LIU CHUN-WEI, YANG DAVID J, YU DONG-FANG, KIM, E., EDMUND, LIU, CHUN-WEI, YANG, DAVID, J., YU, DONG-FANG
Applicants: KIM E EDMUND, LIU CHUN WEI, REGENTS BOARD OF, YANG DAVID J, YU DONG FANG, BOARD OF REGENTS, KIM, E., EDMUND, LIU, CHUN-WEI, YANG, DAVID, J., YU, DONG-FANG
Application year: 2001
Main classification: A61K51
IPC codes: A61K51, C07D233, C07D409, C07D475, C07H23