Synthesis and evaluation of 4-bromo-1-(3-[18F]fluoropropyl)-2-nitroimidazole with a low energy LUMO orbital designed as brain hypoxia-targeting imaging agent

In order to develop new imaging markers for brain hypoxia, 4-bromo-1-(3-fluoropRopyl)-2-nitroimidazole (4-BrFPN) was designed based on molecular orbital calculations, synthesized and labeled with fluorine-18 as a lipophilic nitroimidazole analog with a lower energy LUMO orbital than those for fluoromisonidazole (FMISO) and 1-(3-fluoropropyl)-2-nitroimidazole (FPN). In an in vitro radiosensitization study, the sensitizer enhancement ratio for 4-BrFPN was found to be 1.65 at a 1 mM concentration, in comparison to 1.81 for FMISO. The preparation of F-18-labeled 4-BrFPN (4-(BrFPN)-F-18) was achieved by [F-18]fluoride ion displacement reaction of the tosylate precursor, in a reasonable radiochemical yield (33%, not corrected for decay). Metabolites in tumor and muscle extracts from methylcholanthrene-induced fibrosarcoma mice, as well as the tissue distribution of 4-(BrFPN)-F-18 in normal rats, were studied. The initial uptake into rat brain of 4-(BrFPN)-F-18 was significantly higher relative to F-18-labeled FMISO ((FMISO)-F-18), followed by a rapid washout from the brain. The tumor uptake of 4-(BrFPN)-F-18 was somewhat enhanced compared to those obtained with (FMISO)-F-18 and F-18-labeled FPN ((FPN)-F-18), but with lower tumor localization than 18FMISO. Analyses of tumor and muscle extracts showed metabolites remaining base line on the radio-TLC plates, and they were produced to a greater extent in tumor than muscle. The use of two drugs which increase hypoxic cell fraction in tumor, hydralazine or nitro-L-arginine, produced a significant increase in tumor levels of 4-(BrFPN)-F-18, suggestive of a hypoxic mechanism of accumulation. The results imply that lowering of the LUMO energy of a molecule alone is not sufficient to improve its biodistribution properties for better imaging of regions of hypoxia.