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 I mM 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.
Yamamoto
Fumihiko
F
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Aoki
Mizuho
M
Furusawa
Yoshiya
Y
Ando
Koichi
K
Kuwabara
Yasuo
Y
Masuda
Kouji
K
Sasaki
Shigeki
S
Maeda
Minoru
M
D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006224:Cricetinae; D004583:Electrons; D005462:Fluorine Radioisotopes; D002534:Hypoxia, Brain / Q000000981:diagnostic imaging*; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000031:analogs & derivatives*; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
C468310:4-bromo-1-(3-fluoropropyl)-2-nitroimidazole; D005462:Fluorine Radioisotopes; D008055:Lipids; D009593:Nitroimidazoles; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole