title: Non-beta-oxidizable omega-[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-beta-oxidazable no-carrier-added omega-[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-beta-oxidizable omega-[18F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated omega-oxidation. Therefore, labeling at the (omega-3) carbon was proposed to provide a more stabile 18F-label. Defluorination of the (omega-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, (omega-3) labeling with 18F is preferable to omega labeling of non-beta-oxidizable LCFA analogs.
authors.affiliation: Institut für Chemie 1, Forschungszentrum Jülich, Germany.
authors.forename: T R
authors.initials: TR
authors.lastname: DeGrado
authors.forename: D C
authors.initials: DC
authors.lastname: Moka
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014055:Tomography, Emission-Computed
chemical_list: D005227:Fatty Acids; D005462:Fluorine Radioisotopes; D003577:Cytochrome P-450 Enzyme System