Preliminary evaluation of 15-[F-18]fluoro-3-oxa-pentadecanoate as a PET tracer of hepatic fatty acid oxidation

The liver is an important site of fat oxidation. Abnormalities of hepatic m itochondrial fatty acid oxidation (HMFAO) are associated with obesity, type II diabetes, alcoholic hepatitis, and nonalcoholic steatohepatitis. Noninv asive assessment of HMFAO by PET has been impeded by the lack of a specific radiotracer. Methods: No-carrier-added 15-[F-18]fluoro-3-oxapentadecanoate (FOP) was synthesized and evaluated in living rats and isolated rat livers . Results: FOP showed high uptake and slow clearance of radioactivity from livers in living rats. Inhibition of HMFAO by pretreatment of fasting rats with the carnitine palmitoyltransferase-I (CPT-I) inhibitor reduced the liv er-to-blood ratio by 64%. In isolated rat livers, perfused in normoxic (95% O-2) and hypoxic (15% O-2) conditions with glucose (5 mmol/L) and palmitat e (0.15 mmol/L), the externally measured kinetics of FOP showed reversible binding in tissue. The kinetics were adequately fit by a catenary e-compart ment model for estimation of tracer distribution volumes (DVs). The DVs of both compartments were found to correlate with fractional palmitate oxidati on rate (FPOR) in experiments in normoxic and hypoxic conditions. The corre lation was particularly strong for the slower second compartment (DV2 [mL/g dry weight] = 34.1 FPOR [mL/min/g dry weight] - 0.7, r = 0.89). Relatively small levels of diffusible metabolites of FOP were formed in vivo and in i solated rat liver. Conclusion: The selective uptake of FOP by liver and the high sensitivity of hepatic FOP DV to changes of HMFAO with CPT-I inhibiti on and hypoxia suggests potential usefulness for the 3-oxa fatty acid analo g in assessments of hepatic mitochondrial oxidation of exogenous fatty acid s with PET. These data emphasize that further studies are required to clari fy the intracellular disposition of FOP in the liver and test its validity as a tracer of HMFAO over a broad range of conditions.