8-[18F]fluorooctanoic acid and its beta-substituted derivatives as potential agents for cerebral fatty acid studies: synthesis and biodistribution.
Fluorine-18 labeled analogs of 8-fluorooctanoic acid and its structurally modified derivatives with methyl or gem-dimethyl branching or with oxygen substitution at the C3 position were prepared using nucleophilic substitution of the tosylate precursors by [18F]fluoride ion, for evaluation as tracers for cerebral fatty acid metabolism. Tissue distribution studies in rats showed low brain uptakes of these 18F-labeled fatty acid analogs with poor brain-to-blood ratios of activity. The oxygen-substituted analog did not show any significant accumulation of radioactivity in most tissues. The initial brain uptake of activity after injection of ethyl 8-[18F]fluorooctanoate and its free acid remained virtually unchanged over an extended time period, beta-Monomethyl and beta-gem-dimethyl branched analogs had similar brain uptake at the early time period, but they showed rapid clearance of activity from the brain. TLC analysis showed no incorporation of 8-[18F]fluorooctanoic acid and its beta-dimethyl analogs into brain lipids. It was also shown in the metabolite analysis that the labeled metabolites produced from 8-[18F]fluorooctanoic acid are found in blood, and that they could enter the brain to a significant degree. On the contrary, such radioactive metabolites could not be found in the brain in the experiment with the beta-gem-dimethyl branched analog. Thus, the present studies showed that retention of radioactivity in the brain with 8-[18F]fluorooctanoic acid derivatives is mainly attributable to their radioactive metabolites, and that the rapid clearance of beta-branched analogs from the brain is due to the lack of availability as substrates in the cerebral fatty acid metabolism.
Nagatsugi
F
F
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Sasaki
S
S
Maeda
M
M
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002210:Caprylates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002855:Chromatography, Thin Layer; D005227:Fatty Acids / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D002210:Caprylates; D005227:Fatty Acids; D005462:Fluorine Radioisotopes; C108006:8-fluorooctanoic acid