Synthesis and preliminary evaluation of 18-¹⁸F-fluoro-4-thia- oleate as a PET probe of fatty acid oxidation

Fatty acid oxidation (FAO) is a major energy-providing process with important implications in cardiovascular, oncologic, neurologic, and metabolic diseases. A novel 4-thia oleate analog, 18-¹⁸F-fluoro-4-thia-oleate (¹⁸F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-¹⁸F-fluoro-4-thia-palmitate (¹⁸F-FTP) as an FAO probe. Methods: ¹⁸F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with ¹⁸F-FTO and ¹⁸F-FTP in rats. Results: A practical synthesis of ¹⁸F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of ¹⁸F-FTO (0.70 ± 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of ¹⁸F-FTP at 30 min after injection. At 2 h, myocardial uptake of ¹⁸F-FTO was maintained, whereas ¹⁸F-FTP uptake in the heart was 82% reduced. Similar to ¹⁸F-FTP, ¹⁸F-FTO uptake by the heart was approximately 80% reduced at 30 min by pretreatment of rats with the CPT-I inhibitor etomoxir. Folch-type extraction analyses showed 70-90% protein-bound fractions in the heart, liver, and skeletal muscle, consistent with efficient trafficking of ¹⁸F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of ¹⁸F-FTO and of ¹⁸F-FTP into the heart and liver. Images of ¹⁸F-FTO accumulation in the rat myocardium were clearly superior to those of ¹⁸F-FTP. Conclusion: ¹⁸F-FTO is shown to be a promising metabolically trapped FAO. probe that warrants further evaluation.