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标题：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
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作者：Fumihiko Yamamoto ; Mizuho Aoki ; Yoshiya Furusawa 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2002
卷号：25
期号：5
页码：616-621
DOI：10.1248/bpb.25.616
出版社：The Pharmaceutical Society of Japan
摘要：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 m M concentration, in comparison to 1.81 for FMISO. The preparation of ¹⁸F-labeled 4-BrFPN (4-Br¹⁸FPN) was achieved by [¹⁸F]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-Br¹⁸FPN in normal rats, were studied. The initial uptake into rat brain of 4-Br¹⁸FPN was significantly higher relative to ¹⁸F-labeled FMISO (¹⁸FMISO), followed by a rapid washout from the brain. The tumor uptake of 4-Br¹⁸FPN was somewhat enhanced compared to those obtained with ¹⁸FMISO and ¹⁸F-labeled FPN (¹⁸FPN), 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-Br¹⁸FPN, 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.
关键词：nitroimidazole;fluorine-18;brain tissue;tumor;biodistribution