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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
  • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
  • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
  • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/041—Heterocyclic compounds
  • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
  • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention is directed to delivering an agent with oxygen mimetic properties to hypoxic tissue such as tumor cells and affecting the growth of the hypoxic tissue.
• the agents of the present invention selectively target and incorporate into hypoxic tissue, and by inherent properties of the agent itself or through the cytotoxic action of agents conjugated to the oxygen mimetic agent, accomplish growth inhibition of the hypoxic tissue and/or cell killing.
• the diagnostic compositions and methods include oxygen mimetic agents conjugated to radionuclides, such as Technicium-99, Iodine-123, or Iodine-131, to provide a means of imaging the cancerous tissue. Comparison of the amounts of hypoxic tissue before and after various cancer therapies provides a measure of treatment efficacy.
• Radiotherapy can involve direct exposure of the cancerous tissue to radiation delivered by a targeting agent to the tumor site with minimal exposure of
• C0NFIRMATI0N COPY normal tissue to radiation damage or radiation delivered to general areas of the body with consequent increased exposure of normal tissue to radiation.
• Chemotherapy involves delivery of cytotoxic agents to the tumor site with the aim of preferentially destroying cancerous tissue over normal tissue.
• the literature is replete with examples of side effects to both radiation therapy and chemotherapy.
• Immunotherapy has been studied extensively over the past several years with varied results, depending on the approach taken. Unfortunately, it is generally the case that tumor specific antibodies will not in and of themselves exert sufficient anti-tumor effects to make them useful in cancer therapy. In contrast with their efficacy in lymphomas, immunotoxins have proven to be relatively ineffective in the treatment of solid tumors such as carcinomas.
• hypoxia defines a metabolic state in which the concentrations of oxygen in tissue are lower than required to sustain normal cellular metabolism yet are not totally lacking oxygen, as would be found in a state of anoxia.
• Tissues are hypoxic if molecular oxygen (Oj) levels are below normal, but not at zero (anoxia).
• Oj molecular oxygen
• radiobiological hypoxia is most pronounced at 0 2 levels below 1000 ppm (0.1%; ⁇ 0.1 mm Hg p0 2 ) but in other tissues, metabolic effects may be apparent at 0 2 concentrations just below the venous blood concentration ( ⁇ 30 mm Hg p0 2 ).
• Hypoxia may develop in tissues because of transient capillary occlusion, vascular or arterial damage, or inadequate angiogenesis.
• Tumor hypoxia occurs through several mechanisms. The most readily apparent mechanism is rapid, uncontrolled growth of the tumor tissue such that the existing nutritional stores and blood supply (oxygen) are insufficient to support cellular processes.
• Oxygen deficiency is associated with a number of physiological and pathological conditions.
• the concentration of oxygen in healthy cells varies substantially from tissue to tissue, with lowest concentrations occurring in cells farthest from capillaries in the liver.
• hypoxia may occur as a result of aggressive tissue proliferation together with inadequate angiogenesis, a common condition in solid tumors (cancer).
• Hypoxia may also occur as a result of ischemia (decreased blood supply) because of vascular rupture (stroke), vascular blockage (heart attack) or vascular or arterial disease (diabetes).
• stroke vascular rupture
• vascular blockage heart attack
• diabetes vascular or arterial disease
• HGF-1 Hypoxia-Inducible Factor alpha
• VEGF Vascular Endothelial Growth Factor
• FGF Fibroblast Growth Factor
• angiogenin Hepatocyte Growth Factor
• HGF Hepatocyte Growth Factor
• IL-8 Interleukin-8
• PAF Platelet Activating Factor
• PEGF Platelet-Derived Endothelial Growth Factor
• TGF- ⁇ Transforming Growth Factor- ⁇
• TGF- ⁇ Tumor Necrosis Factor- ⁇
• TGF- ⁇ Tumor Necrosis Factor- ⁇
• TGF- ⁇ Tumor Necrosis Factor- ⁇
• VEGF also known as Vascular Permeability Factor (VPF) is likely the most potent pro-angiogenic molecule of the above list (Brown et al, EXS, 79:233- 269
• tumor cells In response to lower levels of oxygen, tumor cells undergo a "stress response" and display lower radiation sensitivity. This oxygen effect in clinical radiotherapy has proven to be a significant obstacle to effective treatment. Under conditions of low oxygen levels, cell phenotypes are expressed which favor tumor progression through mechanisms involving resistance to therapy in addition to increased angiogenesis.
• Oxygen-deficient cells require approximately three times more radiation for a lethal effect than for fully oxygenated cells. This Oxygen effect' is due to the reactivity of oxygen with molecules that have unpaired electrons (free radicals) and to the reactivity of singlet oxygen and other oxygen radical species. Reaction between oxygen and free radicals results in the formation of peroxy species which can inhibit cellular repair mechanisms, and which can react with other molecules such as DNA to inactivate them. Radiation therapy generates high concentrations of short-lived reactive species such as solvated electrons, hydrogen radicals and hydroxy radicals.
• cancer cells Exposure of cancerous tissue to high levels of oxygen reverses the resistance of the tumor to radiation therapy. In the presence of normal to high levels of oxygen, cancer cells initiate a rapid growth phase, essential for efficient killing by the radio- therapeutic agent. Under such circumstances the cancer cells divide rapidly and release cancer-specific molecules into the blood stream, detectable using standard assay techniques.
• hypoxic tissue such as solid tumors
• a variety of compounds which selectively incorporate into the hypoxic cells.
• IAZA iodoazomycin arabinoside
• This molecule has been shown to selectively incorporate into hypoxic cells of solid tumors such as small-cell lung carcinoma, non-small-cell lung carcinoma, glioblastoma, and cancers of the Head and Neck.
• IAZA radiolabeled IAZA as a diagnostic probe to image hypoxic tumors.
• 123 I-LAZA was well tolerated in individuals with various malignancies when used as a tool to image hypoxic tissue (Urtasun et al, British Journal of Cancer, Supplement, 27:S209-S212, 1996). The doses used in imaging are much lower than would be used in therapy.
• Auger-electron emitters such as 125 Iodine ( 125 I) in comparison to beta-emitters such as 131 I
• Higher doses of the Auger-electron emitters are tolerated by the recipient resulting in improved therapeutic outcome.
• the lower toxicity of the Auger- emitters may be due to the short path length of the low-energy electrons (micrometers) versus the longer path length of the beta-emitters (millimeters). Although Auger- emitters are better tolerated (i.e.
• treatment efficacy is greatly improved if the agents carrying the Auger-emitters are internalized by the tumor cell leading to improved targeting of the tumor cell DNA.
• Targeting of hypoxic tissue with Auger-electron labeled oxygen mimetics such as 125 I- IAZA selectively damages the DNA of the hypoxic tissue in turn preventing release of pro-angiogenic factors such as HIF-1 and VEGF.
• 131 I-conjugated oxygen mimetic i.e. 131 I-IAZA
• 131 I-IAZA due to its slightly longer radiation path length, provides better therapeutic efficacy by destroying not only the hypoxic tissue responsible for the uptake of the agent, but also tissue that is immediately adjacent to the cancer tissue. This tissue is most often cancerous tissue that is slowly progressing to a hypoxic state.
• MRI Magnetic Resonance Imaging
• X-ray radiographic analysis
• CAT scans manual palpation
• the current invention encompasses methods for rapidly determining the effectiveness of cancer therapy through the use of oxygen mimetic agents conjugated to radionuclides.
• the present invention relates to delivery of oxygen mimetic molecules, such as
• IAZA to hypoxic tissue, such as a tumor mass, as a means to selectively reduce cell growth and/or kill the target tissue.
• the present invention also relates to the use of oxygen mimetic molecules bound to radionuclides as a means of monitoring the efficacy of various cancer therapies.
• a hypoxic state in tumor tissue leads to enhanced resistance to radio- and chemotherapeutic agents, in addition to initiation of new blood vessel growth through the release of various agents that promote angiogenesis. Delivery of an agent that specifically targets hypoxic tissue and also has oxygen mimetic properties is most desirable. Addition of the oxygen mimetic molecule to the hypoxic tissue (e.g. tumor) interferes with the natural compensatory mechanism for hypoxic stress (i.e.
• the oxygen mimetic molecule can be delivered in a conjugated or un-conjugated form.
• Preferred agents to which the oxygen mimetic is conjugated include cytotoxic agents, radioactive agents and oligonucleotides.
• a radio-conjugated oxygen mimetic e.g. 125 I-IAZA, 131 I-IAZA
• a radio-conjugated oxygen mimetic e.g. 125 I-IAZA, 131 I-IAZA
• Typical vascularized tumors are the solid tumors, particularly carcinomas, which require a vascular component for the provision of oxygen and nutrients.
• Exemplary solid tumors to which the present invention is directed include, but are not limited to, carcinomas of the lung, breast, ovary, stomach, pancreas, larynx, esophagus, testes, liver, parotid, biliary tract, colon, rectum, cervix, uterus, endometrium, kidney, bladder, prostate, thyroid, squamous cell carcinomas, adenocarcinomas, small cell carcinomas, melanomas, gliomas, neuroblastomas, and the like.
• the present invention provides compositions and methods for delivering agents with oxygen mimetic properties to hypoxic tissue, such as tumor cells, thereby affecting the growth of the hypoxic tissue.
• the agents with oxygen mimetic properties are nitroimidazole or nitroimidazole-like compounds, and they are allowed to incorporate in the hypoxic tissue, thus inducing an altered state.
• the altered state leads to a mediation in the amount of released pro-angiogenic factors.
• mediation refers to an increase, a decrease, or combinations thereof.
• a method for measuring the effectiveness of therapy intended to kill neoplastic tissue or cells in a mammal comprising the steps of obtaining molecules with oxygen mimetic properties, which bind preferentially to hypoxic cancerous tissue, the oxygen mimetic agent being labeled; contacting the labeled oxygen mimetic with tissue of a mammal that has received therapy to kill neoplastic cells in vivo; and determining the effectiveness of therapy by measuring the binding of the labeled oxygen mimetic agent to the remaining hypoxic cancerous tissue.
• the oxygen mimetic agent binds specifically to hypoxic cancer tissue or cells, and the contacting step preferably comprises administering the labeled oxygen mimetic to a mammal in vivo.
• Preferred labels include radionuclides, magnetic resonance enhancing agents, and radiopaque materials, and preferred methods for measuring binding or incorporation of labeled oxygen mimetic to hypoxic tissue include imaging techniques including scintigraphic, magnetic resonance and radiographic imaging.
• the present invention provides compositions and methods for monitoring the efficacy of cancer therapy by delivering labeled agents with oxygen mimetic properties to hypoxic tissue, such as tumor cells, pre- and post-treatment, thereby providing a measure of tumor tissue reduction based on the binding or incorporation of the oxygen mimetic agent into the remaining hypoxic neoplastic tissue.
• the present invention also provides compositions and methods for measuring hypoxia in vivo, preferably hypoxia related to and/or associated with cancer, by delivering labeled agents with oxygen mimetic properties to hypoxic tissue, such as tumor cells, pre- and post-treatment, thereby providing a measure of localized hypoxia based on the binding or incorporation of the oxygen mimetic agent into the remaining hypoxic tissue (e.g., neoplastic tissue).
• hypoxic tissue such as tumor cells
• pre- and post-treatment thereby providing a measure of localized hypoxia based on the binding or incorporation of the oxygen mimetic agent into the remaining hypoxic tissue (e.g., neoplastic tissue).
• oxygen mimetic agent is constructed such that the agent is preferentially incorporated into hypoxic tissue. In a preferred embodiment of the invention, the agent would preferentially incorporate into tumor cells, in vivo.
• oxygen mimetic agents suitable for radiolabeling include, but are not limited to: IAZA, iodoazomycin galactoside (IAZG), iodoazomycin pyranoside (IAZP), fluoroiodoazomycin pyranoside (FIAZP), IAZGlu (a glucoside), l-(4-iodo-4- deoxylyxopyranosyl)-2-nitroimidazole (IAZLP), iodoazomycin riboside (IAZR), iodovinylmisonidazole (IVM), 2-nitroimidazolyl)-l-(iodo-4-hydroxyphenyl) ethanols (NIHE's), 2-(2-nitroimidazolyl)iodohydroxyacetophen
• the oxygen mimetic agent would be radiolabeled with Auger electron emitters.
• Auger-emitters include, but are not limited to: 125 Iodine, 123 Iodine.
• the oxygen mimetic agent would be radio labeled with 131 Iodine.
• Radiopaque materials also may be used to label the oxygen mimetic agent. Suitable radiopaque materials include, but are not limited to iodine compounds, barium compounds, gallium compounds, and thallium compounds.
• radiopaque materials include barium, diatrizoate, ethiodized oil, gallium citrate, iocarmic acid, iocetamic acid, iodamide, iodipamide, iodoxamic acid, iogulamide, iohexol, iopamidol, iopanoic acid, ioprocemic acid, iosefamic acid, ioseric acid, iosulamide meglumine, iosumetic acid, iotasul, iotetric acid, iothalamic acid, iotroxic acid, ioxaglic acid, ioxotrizoic acid, ipodate, meglumine, metrizamide, metrizoate, propyliodone, and thallous chloride. Materials that can be detected by or that enhance the effects of magnetic resonance imaging equipment also may be conjugated to the oxygen mimetic agent
• alpha-emitting and beta-emitting radionuclides may be used.
• Such compounds include, but are not limited to, 1-131, Y- 90, Cu-67, Au-198, and P-32.
• administering refers to any action that results in exposing or contacting a composition containing a binding agent with a pre-determined cell, cells, or tissue, typically mammalian. Administering may be conducted in vivo, in vitro, or ex vivo. For example, a composition may be administered by injection or through an endoscope or catheter. Administering also includes the direct application to cells of a composition according to the present invention. For example, during the course of surgery, the vasculature of tumor or hyperplastic tissue may be exposed. In accordance with an embodiment of the invention, the exposed cells or vasculature may be exposed directly to a composition of the present invention, e.g., by washing or irrigating the surgical site, and/or the cells.
• compositions may also include pharmaceutically acceptable carriers.
• Pharmaceutically acceptable carriers include but are not limited to saline, sterile water, phosphate buffered saline, and the like. Other buffering agents, dispersing agents, and inert non-toxic substances suitable for delivery to a patient may be included in the compositions of the present invention.
• the compositions may be solutions suitable for administration, and are typically sterile and free of undesirable particulate matter.
• the compositions may be sterilized by conventional sterilization techniques.
• the therapeutic or diagnostic agent may be introduced into the patient by an intravenous, subcutaneous, intraperitoneal, intrathecal, intravesical, intradermal, intramuscular, or intralymphatic route.
• the composition may be in solution, tablet, aerosol, or multi-phase formulation forms.
• Liposomes, long-circulating liposomes, immunoliposomes, biodegradable microspheres, micelles, or the like may also be used as a carrier, vehicle, or delivery system.
• the clinician may compare the responses associated with these different routes in determining the most effective route of administration.
• the invention should not be limited to any particular method of introducing the binding agent into the patient.
• Administration may be once, more than once, and over a prolonged period.
• compositions of this invention may be used for patients in a serious disease state, i.e., life threatening or potentially life-threatening, excesses of the binding agent may be administered if desirable.
• Actual methods and protocols for administering pharmaceutical compositions, including dilution techniques for injections of the present compositions, are well known or will be apparent to one skilled in the art. Some of these methods and protocols are described in Remington's Pharmaceutical Science, Mack Publishing Co. (1982).
• composition may be administered in combination with other agents or regimens to effect tumor arrest, regression or killing.
• the composition may be administered in the presence of agents that enhance the uptake of the composition such as permeating agents.
• agents that enhance the uptake of the composition such as permeating agents.
• liposomes, nanospheres, micelles, or microspheres may be used to administer a composition, and that such administration may result in a therapeutically desirable benefit.
• oxygen mimetic refers generally to the group of molecules known as nitroimidazoles, which undergo reversible 1-electron reductions in hypoxic tissue. One or more of these reduced products can react chemically with cellular components to form non-diffusible adducts.
• hypoxic tissue refers to any tissue, including cancerous tissue that contains lower levels of oxygen (e.g., ⁇ 10 mm Hg) than normally found in that tissue.
• adjunct therapy refers to any treatment used in combination with, or as follow-up to, an existing therapeutic regimen.
• an existing chemotherapeutic regimen such as cisplatin, cyclophosphamide and doxorubicin, as an example, could be concomitantly or treated in follow-up with the oxygen mimetic therapy of the present invention.
• azomycin arabinoside was prepared by coupling azomycin to a 1-bromo-protected sugar. Azomycin arabinoside was iodinated using the triphophine/iodine method of Jette et al (Radiation Research, 105:169-179, 1986).
• Azomycin arabinoside was synthesized by coupling the corresponding protected 1-bromo sugar to azomycin using a modification of the published procedure. Although the ⁇ -bromo anomer was used to produce the ⁇ -nucleoside, and contrary to earlier reports of ⁇ -nucleoside formation, the ⁇ -nucleoside has been confirmed to be the major product of the coupling and, when C5 '-iodinated, to be the product referred to in the literature as IAZA.
• IAZA l- ⁇ -D-(5-Iodo-5-deoxy-arabinofuranosyl)-2-nitroimidazole
• IAZR and IAZA Conformational differences between IAZR and IAZA, resulting from the change in configuration at C-l' (from ⁇ to ⁇ ) and C-2' (from 'ribo - down' in IAZR to 'arabino - up' in IAZA) introduced substantial physicochemical changes.
• the P of IAZA (4.98) is double that for IAZR, but the in vitro rate of hypoxia-dependent adduct formation was identical to IAZR rates, and radiosensitization and cytotoxicity properties were similar between the two nucleosides.
• tumor cells such as EMT-6 (mouse fibrosarcoma), LnCAP (human prostate cancer) and MCF-7 (human breast carcinoma) under hypoxic conditions demonstrated selective uptake of oxygen mimetic molecules such as IAZA, 131 I-LAZA, and 125 I-IAZA.
• I-IAZA is used to image various tumors in human subjects and demonstrates selective incorporation in these hypoxic tissues. Imaging studies will be performed in 5 subjects with tumors demonstrating defined areas of hypoxia.
• I-IAZA is administered by slow intravenous injection; in previous studies no side effects to the injection have been noted; 200-300 MBq will be administered and the patient monitored after injection with measurement of pulse and blood pressure and observation. Planar whole body images will be acquired immediately after injection and at 4, 24, 48, 72 and 96 hours after injection. Each set of images will take approximately 30 minutes. No SPECT images will be required for this protocol. Images will be acquired on a Marconi Axis gamma camera interfaced to an Odyssey computer. A high energy collimator will be used for all images and all images acquired to time.
• Dosimetry calculations will be performed using the MIRD formalism and patterns of uptake and distribution reviewed from the derived images.
• the key data derived from this study will be (a) retention of 131 I-IAZA in tumor and (b) whole body dosimetry calculations.
• a successful outcome will be demonstration of prolonged uptake and retention, low whole body dosimetry and adequate tumor dosimetry.
• An oxygen mimetic agent such as that produced in Example 1 can be labeled with 1-125, 1-131 or 1-123 by standard procedures as outlined by Weibe et al (US patent 5401490).
• 131 I-IAZA is used to image solid tumors such as tumors of the Head and Neck, prostate tumors, small cell lung carcinomas, and the like, prior to initiating cancer therapy. Radiographic analysis using the labeled oxygen mimetic provides a baseline reading of the location and extent of hypoxic neoplastic tissue. The subject is then exposed to the anti-tumor therapy and after waiting an appropriate period of time for the therapy to have taken effect, as would be known to those skilled in the art, the tumor is again imaged to measure the incorporation of the 131 I-IAZA into the tumor tissue. Reduction in 131 I-IAZA-incorporation is indicative of a desirable therapeutic regimen.
• I-IAZA-incorporation may prompt higher dosage of the therapeutic agent or abandoning of the current therapy in favor of a more promising therapy. In this way, therapy can be adjusted on an individual basis to maximize tumor killing while minimizing undesirable treatment side effects.
• Example 7 IAZA has been studied in a variety of experimental pathologies.
• PDT photodynamic therapy
• 123 IAZA uptake in regions of PDT-induced hypoxia showed an inverse correlation with 99ra Tc-HMPAO uptake.
• This provided strong evidence for hypoxia-selective binding of 123 IAZA.
• These conclusions were recently confirmed in autoradiographic studies of a rat model of cerebral occlusion, in which dual radionuclide autoradiography clearly depicted uptake of 125 IAZAin ischemic areas and (mutually exclusively) uptake of 99m Tc-HMPAO in well-perfused regions.
• Preliminary imaging studies in a surgical model of canine myocardial ischemia showed uptake of 123 IAZA in ex vivo images but not in in vivo images taken 4 h after dosing.
• IAZA given after iv 125 IAZA, produce a drastic 'wash-out' effect, lowering blood levels dramatically with out affecting tumor uptake to produce tumo ⁇ blood ratios of 8.7 at 4 h (compared to 6.3 in controls) in the murine EMT-6 model.
• radiopharmacokinetic and radiotracer kinetics in human volunteers who received iv doses of 123 IAZA ranging form 0.1 to 10 mg show no discernible difference in plasma clearance and whole body elimination over this 1000-fold concentration range.
• Example 9 125 IAZR was obtained by exchange from Na 125 I in DMF at 84° for 3 h
• IAZR radiochemical yield 85%
• Introduction of iodine also increased protein binding (from ⁇ 1% for Miso and AZR, to 20% for IAZR); radiosensitizer efficacy was increased by 2-3 times over AZR (5-10 times over Miso), and cytotoxicity was about 25 times greater than Miso.
• the rate of adduct formation by IAZR was 2.5-3 times greater than for Miso at concentrations from 10- 100 ⁇ M.
• Example 10 l-(6-Iodo-6-deoxy- ⁇ -D-galactopyranosyl)-2-nitroimidazole (LAZG) was designed to have a lower P than IAZA. This was accomplished by using a hexose rather than the pentose sugars of IAZR and IAZA.
• the non-iodinated nucleoside (AZG) was prepared by coupling the blocked ⁇ -bromogalactose with azomycin, and IAZG was prepared by iodination with triphenylphosphine and iodine, using standard work-up procedures.
• LAZG was reported to have a P of 0.57 and hypoxia-dependent binding rates somewhat lower than for IAZA and Miso in EMT-6 cells in vitro.
• IAZG exchange labeling
• Example 11 l-(4-Iodo-4-deoxy-L-xylopyranosyl)-2-nitroimidazole (IAZP) was synthesized by coupling the protected arabinopyranosyl bromide to azomycin, followed by deblocking and iodination using triphenylphosphine and iodine, with the appropriate work-up.
• IAZP l-(4-Iodo-4-deoxy-L-xylopyranosyl)-2-nitroimidazole
• IAZP differs from IAZA in that the sugar is in the pyranosyl (5-carbons and oxygen in the ring) form rather than the furanosyl form, so that both compounds have the C2' & C3' 'arabino' configuration, but significantly, the iodo substituent is on C4', a secondary alkyl iodide in IAZP, rather than as a primary alkyl iodide. This alteration was introduced in order to stabilize the nucleoside against deiodination, without greatly affecting other properties.
• 2-nitroimidazole nucleosides with lower P values than IAZA include the glucoside, the 2'-I-arabinoside and the glucuronide.
• the glucoside includes the glucoside, the 2'-I-arabinoside and the glucuronide.
• IAZGlu a hexose glycoside like IAZG
• the other new nucleoside, l-(4-iodo-4-deoxylyxopyranosyl)- 2-nitroimidazole (IAZLP) is slightly less lipophilic than IAZGlu, intermediate in binding rate and produced the lowest of the reported tumor: blood ratios in a tumor model.
• the radioiodinated 2-nitroimidazoles comprise the main body of the literature that deals with agents for scintigraphic detection of tissue hypoxia. It is clear from the literature that ring-halogenated nitroimidazoles (radioiodine or radiobromine) are not chemically or metabolically labile (Br-Miso; 4-1-5- nitroMHPI) and/or have low electron affinity (Iodometronidazole; 4-I-5-nitroMHPI).
• An advantage of the side-chain-halogenated azomycin derivatives is their relatively narrow range of E ⁇ 's, within the range for oxygen-reversible reductions to occur in hypoxic tissues. The molecular design then becomes primarily a matter of adjusting (non-reductive) metabolic and pharmacokinetic properties. Compounds reported to date fall into two general categories viz., misonidazole congeners and azomycin glycosides.

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