Appl. Radial. ht . Vol. 40, No. 2, pp. 117-126, 1989 ht . J. Radial. Appl. hsr r um. Par r A Printed in Great Britain. All rights reserved 0883-2889189 $3.00 + 0.00 Copyright 0 1989 Pergamon Press plc No-carrier-added Synthesis of 3-[18F]Fluoro- 1-(2-nitro- 1 -imidazolyl)-2-propanol. A Potential PET Agent for Detecting Hypoxic but Viable Tissues D.-R. HWANG, C. S. DENCE, T. A. BONASERA and M. J. WELCH* Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, U.S.A. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONML (Received 5 July 1988) Four different approaches towards the synthesis of [‘8F]FMIS0 have been studied. The first approach was based on the reaction of epoxide 4 and [‘*F]fluoride. Both specific activity and radiochemical yield (< 1%) for [‘8F]FMIS0 were low. Two new approaches, starting with compounds 8 and 9, have failed to give [‘sF]FMISO. The fourth approach, based on the reaction of [‘8F]epifluorohydrin 10, prepared from Tosylate 13 and [‘8F]KF/Kryptofix 222, has provided a reliable, no-carrier added synthesis of [‘8F]FMIS0. The product was obtained in a radiochemical yield of 7-12% at end-of-synthesis (based on [‘8FJfluoride) with a specific activity of 2400 Ci/mmol and a synthesis time of 1.5 h. Preliminary PET studies suggest that [‘sF]FMISO may be a promising tracer for delineation of ischemic but viable myocardium. Introduction The effectiveness of cancer treatment by ionizing radiation is found to be dependent on the oxygen concentration within the tumor (Gray et al., 1953). Studies confirm that hypoxia does influence the radi- ation sensitivity of some tumors (Urtasun et al., 1976; Henk and Smith, 1977; Bush et al., 1978). To date the presence of hypoxic tissues has been demonstrated in solid tumor (Chapman, 1979; Chapman et al., 1981; Chapman, 1984; Moulder and Rockwell, 1984) and suspected in brain tissues following a stroke (Plum and Pulsinelli, 1986) and in infarcted myocardium (Pike et al., 1982). The use of radiosensitizers in enhancing the efficiencies of radiation treatments of solid tumors has been actively pursued. Two nitroimidazole deriv- atives, namely misonidazole (MISO) (Adams et al., 1976) and metronidazole (METRO) (Asquith et al., 1973), have been widely used (Fig. 1). The former has been the most often used sensitizer due to its higher efficiency of radiosensitization than that of met- ronidazole (Adams et a/., 1976), and its cytotoxicity to the hypoxic cells of tumors (Brown, 1982). In vitro and in vivo metabolic studies of MIS0 indicated the major oxidative metabolites included the hydrolysis product of MISO, demethyl-MISO, *Author for correspondence. and its glucuronide derivatives (Varghese et al., 1976; Flockhart et al., 1978). These oxidative metabolites are eliminated from the body and do not appear to be biologically active (Rauth, 1984). From the structure-activity relationship studies of many nitroheterocyclic compounds in radio- sensitizing hypoxic cells in vitro, the sensitization efficiency is found to depend mainly on the reduction potentials of these compounds (Adams et al., 1976; Adams et al., 1979). Extensive biological and bio- chemical examinations of MIS0 have shown a num- ber of effects related to reductive metabolism (Brown, 1982; Rauth, 1984; McNally, 1982; Kacinki et al., 1980; Chin et al., 1978; Varghese and Whitemore, 1980; Silver et al. 1985; Bump et al., 1983; Mason, 1982; McClelland et al., 1987). The cytotoxicity of MIS0 toward hypoxic cells has been suggested to be due to the binding of the reductive metabolites of MIS0 to macromolecules of hypoxic cells (Varghese and Whitemore, 1980). The formation of adducts between metabolites of MIS0 and cellular macro- molecules was found to be several times more efficient under hypoxic than aerobic conditions. Recently, stable products from reduction of I-methyl-2- nitroimidazoles under neutral conditions by radiation chemical, electrochemical, and chemical techniques, have been identified, and these products may be of biological importance (McClelland et al., 1987). The ability of the metabolites of MIS0 to bind specifically 117