Field of the Invention
Tumor cells are more sensitive to radiation in the presence of oxygen than in its absence Powers et al., 1963). Even a small percentage of hypoxic cells within a tumor could limit response to radiation (Hall, 1988). Hypoxic radioresistance has been demonstrated in many experimental and animal tumors and hypoxia has been directly demonstrated in certain tumor types in man (Moulder et al., 1984; Peters et al., 1982). The occurrence of hypoxia in human tumors has in most cases been inferred from histologic findings and from evidence of hypoxia in animal tumor studies. In vivo demonstration of hypoxia has required tissue measurements with oxygen electrodes and the invasiveness of this technique has limited its application. Most attempts to increase the radiosensitivity of tumors by administration of chemical radiosensitizers have not been successful (Gatenby, et al., 1988; Kayama et al., 1991; Maor et al., 1981). However, there has been no clinically applicable means of demonstrating tumor hypoxia and it has not been possible to identify the patients who could potentially benefit from radiosensitizing therapy. Potential advantages of neutrons over more conventional radiation include a lesser dependence on oxygenation of the tumor and a lower variability of cell neutron sensitivity around the cell cycle.
3-.sup.18 F!Fluoro-1-(2'-nitro-1'-imidazoyl)-2-propanol (.sup.18 F-fluoromisonidazole; FMISO) has been used with positron emission tomography (PET) to differentiate metabolically active hypoxic tumor from well-oxygenated metabolically active tumor. .sup.18 F-FMISO is metabolized by intracellular nitroreductases and acts as a competing electron acceptor at low oxygen levels. The .sup.18 FMISO is reduced and subsequently incorporated into metabolically active hypoxic cells by covalent bonding to various macromolecules. Recent studies have shown that PET, in view of its ability to monitor cell oxygen content through .sup.18 F-FMISO, has a high potential to predict treatment response. (Koh et al., 1992; Valk et al., 1992; Martin et al., 1989; and Rasey et al., 1989.)
Assessment of tumor hypoxia with .sup.18 F FMISO prior to radiation therapy provides a rational means of selecting patients for treatment with chemical radiosensitizing drugs. Such selection of patients permits more accurate evaluation of radiosensitizing drugs, since their use could be limited to patients with hypoxic tumors, who could potentially benefit. In addition, it is possible to differentiate radiotherapy modalities (neutron versus photon radiotherapy) by correlating .sup.18 F!FMISO results with tumor response.
The synthesis of .sup.18 F!FMISO reported by others showed no resemblance to the present inventive methods. Most studies used a two-part, two-step synthetic procedure, whereas the precursor of the present invention has a nitroimidazole moiety. Although there is a great demand in PET for .sup.18 F!FMISO, a simple and efficient synthesis to produce sufficient radioactivity of .sup.18 F!FMISO is difficult. Prior studies used .sup.18 F!epifluorohydrin to react with 2-nitroimidazole (Hwang et al., 1989; Jerabek et al., 1986; Grierson et al., 1989). The reaction takes a longer time (90 min.) and provides a lower radiochemical yield. One aspect of the present invention concerns a more rapid synthesis of .sup.18 F!FMISO.
Three classes of agents have found practical use for therapy against hypoxia tumors (Hall, 1994). These are (1) radiosensitizers of hypoxic cells, (2) chemopotentiation agents and (3) bioreductive drugs. Radiosensitizers are chemical or pharmacologic agents that increase the lethal effects of radiation when administered in conjunction with it. Nitroimidazoles were reported to potentiate the cytotoxic effects when combined with other chemotherapeutic agents (e.g. cisplatin, bleomycin, cyclophosphamide and nitrosourea). Several clinical trials are in progress combining a radiosensitizer with alkylating agents. It would increase the efficiency of chemotherapy if the hypoxia component could be identified by a labeled tracer prior to the therapy. Bioreductive drugs are not radiosensitizers, yet, these drugs are reduced intracellularly in hypoxia cells to form active cytotoxic agents. Three drugs are primarily used in clinical trials. These drugs are mitomycin C, triapazamine (SR4233) and dual-function nitroheterocyclic compounds (RB6145).
Two nitroimidazole analogues (misonidazole and etanidazole) are potent radiosensitizers. In clinical trails, patients with high hemoglobin levels and cancer of the pharynx showed a great benefit from the addition of these analogues (Hall, 1994). However, the dose-limiting toxicity was found to be peripheral neuropathy that progressed to central nervous system toxicity if drug administration was not stopped. This neurotoxicity prevented the use of the drug at adequate dose levels throughout multifraction treatments.
Therefore, it is necessary to develop a more hydrophilic agent than misonidazole. This would allow the agent to have shorter half-life in vivo and, be expected to show less neurotoxicity. Another aspect of the present invention is the synthesis and evaluation of a new 2-nitroimidazole analogue which is more hydrophilic than FMISO and misonidazole. The synthetic scheme is shown in FIG. 6.
USPTO Backgrounds
USPTO Backgrounds