Synthesis and preliminary evaluation of F-18-labeled 4-thia palmitate as aPET tracer of myocardial fatty acid oxidation

Interest remains strong for the development of a noninvasive technique for assessment of regional fatty acid oxidation rate in the myocardium. F-18-la beled 4-thia palmitate (FTP, 16-[F-18]fluoro-4-thia-hexadecanoic acid) has been synthesized and preliminarily evaluated as a metabolically trapped pro be of myocardial fatty acid oxidation for positron emission tomography (PET ). The radiotracer is synthesized by Kryptofix 2.2.2/K2CO3 assisted nucleop hilic radiofiuorination of an iodo-ester precursor, followed by alkaline hy drolysis and by purification by reverse phase high performance liquid chrom atography. Biodistribution studies in rats showed high uptake and long rete ntion of FTP in heart, liver, and kidneys consistent with relatively high f atty acid oxidation rates in these tissues. Inhibition of carnitine palmito yl-transferase-I caused an 80% reduction in myocardial uptake, suggesting t he dependence of trapping on the transport of tracer into the mitochondrion . Experiments with perfused rat hearts showed that the estimates of the fra ctional metabolic trapping rate (FR) of FTP tracked inhibition of oxidation rate of palmitate with hypoxia, whereas the FR of the 6-thia analog 17-[F- 18]fluoro-6-thia-heptadecanoic acid was insensitive to hypoxia. In vivo def luorination of FTP in the rat was evidenced by bone uptake of radioactivity . A PET imaging study with FTP in normal swine showed excellent myocardial images, prolonged myocardial retention, and no bone uptake of radioactivity up to 3 h, the last finding suggesting a species dependence for defluorina tion of the omega-labeled fatty acid. The results support further investiga tion of FTP as a potential PET tracer for assessing regional fatty acid oxi dation rate in the human myocardium. NUCL MED BIOL 27;3:221-231, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.