18F-labeled octanoates as potential agents for cerebral fatty acid studies. The influence of 4-substitution and the fluorine position on biodistribution.
In order to understand the structural features that might lead to an in vivo radiotracer for studying cerebral fatty acid metabolism, 8-[18F]fluorooctanoate derivatives with methyl or gem-dimethyl branching at the C4 position have been prepared. 3-[18F]Fluoro- and 4-[18F]fluorooctanoic acid have also been synthesized for studying the influence of the fluorine position on the in vivo behavior of 18F-labeled octanoic acid analogs. Radiochemical synthesis was achieved by the nucleophilic displacement of a tosylate or mesylate precursor with [18F]fluoride ion. Tissue distribution studies in rats showed low cerebral uptakes of these 18F-labeled fatty acid analogs with poor brain-to-blood ratios. 3-[18F]Fluorooctanoic acid showed considerable defluorination, evident as a high bone activity level. The initial uptake of activity in the brain after injection of ethyl 8-[18F]fluoro-4-methyloctanoate and 4-[18F]-fluorooctanoic acid remained virtually unchanged over an extended time period, similar to that previously observed for the unbranched analogs, ethyl 8-[18F]fluorooctanoate and its free acid. In contrast, the 4-gem-dimethyl branched analog was rapidly and preferentially taken up by the liver. It was shown in the metabolite analysis that labeled metabolites produced from 8-[18F]fluoro-4-methyloctanoic acid were found in blood, and that they could enter the brain to a significant degree. Thus, the present studies showed that radioactivity retention in the brain in the case of the 4-methyl branched analog was mainly attributable to its radioactive metabolites.
Nagatsugi
F
F
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Inoue
F
F
Sasaki
S
S
Maeda
M
M
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002210:Caprylates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D005461:Fluorine; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D002210:Caprylates; D005461:Fluorine; C031492:octanoic acid