Non-β-oxidizable ω-[18F]fluoro long chain fatty acid analogs show cytochrome P-450-mediated defluorination: Implications for the design of PET tracers of myocardial fatty acid utilization

Abstract

The nature of the in vivo defluorination of non-β-oxidizable no-carrier-added ω-[¹⁸F]fluoro long chain fatty acid (LCFA) analogs was studied with the aim of developing PET tracers of LCFA utilization. Extensive defluorination of 15-[¹⁸F]fluoro-3-thia-pentadecanoic acid (FTPA) in mouse was evidenced by radioactivity uptake by bone. [¹⁸F]Fluoride in the blood was verified analytically. Incubations of FTPA in rat-liver homogenates and subcellular fractions thereof showed a strong defluorination process in microsomes which was O₂- and NADPH-dependent. In contrast, defluorination of FTPA was relatively slow in Langendorff perfused rat heart. High bone uptake in mouse was also observed with 14-[¹⁸F]fluoro-13, 13-dimethyl-3-thia-tetradecanoic acid, where gem-dimethyl substitution precludes direct elimination of H¹⁸F. These data indicate that the defluorination of non-β-oxidizable ω-[¹⁸F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated ω-oxidation.

Therefore, labeling at the (ω-3) carbon was proposed to provide a more stabile ¹⁸F-label. Defluorination of the (ω-3)-labeled 13 (R,S)-[¹⁸F]fluoro-3-thia-hexadecanoic acid was lower than that of FTPA in mouse and was independent of O₂ and NADPH in vitro. Thus, (ω-3) labeling with ¹⁸F is preferable to ω labeling of non-β-oxidizable LCFA analogs.