8-[¹⁸F]fluorooctanoic acid and its β-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. β-Monomethyl and β-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 β-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 β-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 β-branched analogs from the brain is due to the lack of availability as substrates in the cerebral fatty acid metabolism.