Synthesis and Preliminary Evaluation of 18-¹⁸F-Fluoro-4-Thia-Oleate as a PET Probe of Fatty Acid Oxidation

Abstract

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, 18-18 F-fluoro-4-thia-oleate ( 18 F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-18 Ffluoro-4-thia-palmitate ( 18 F-FTP) as an FAO probe. Methods: 18 F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with 18 F-FTO and 18 F-FTP in rats. Results: A practical synthesis of 18 F-FTO was developed, providing a radiotracer of high radiochemical purity (.99%). In fasted rats, myocardial uptake of 18 F-FTO (0.70 6 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of 18 F-FTP at 30 min after injection. At 2 h, myocardial uptake of 18 F-FTO was maintained, whereas 18 F-FTP uptake in the heart was 82% reduced. Similar to 18 F-FTP, 18 F-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 18 F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of 18 F-FTO and of 18 F-FTP into the heart and liver. Images of 18 F-FTO accumulation in the rat myocardium were clearly superior to those of 18 F-FTP. Conclusion: 18 F-FTO is shown to be a promising metabolically trapped FAO probe that warrants further evaluation.

Synthesis and preliminary evaluation of an 18 F-labeled oleic acid analog for PET imaging of fatty acid uptake and metabolism

“…To date, FA analogs with 4-thia substitutions appear to be the most sensitive analogs, because their Co-A esters are substrates for CPT-I mediated transesterification prior to transport into the mitochondria [24]. Additionally, radiofluorinated oleate analogs showed superior imaging properties in the rat heart relative to radiofluorinated palmitate-based agents [8,16,24].…”

“…The blood clearance of the compound was significantly slower than its non-clicked analog, 18 7% radiochemical yield (non-decay corrected), and > 90% radiochemical purity [7].…”

“…Therefore, we adopted the copper-catalyzed alkyne azide cycloaddition reaction to synthesize a clicked 4-thia-oleate analog ( 18 F-6) in order to explore the influence of the -terminal modification of the fatty acid with the triazole group. We also synthesized 18 F-FTO for comparison, because it has been previously shown in rat heart to have good sensitivity to FAO and have high target tissue uptake [24].…”

“…mechanisms [15,24,25]. To date, FA analogs with 4-thia substitutions appear to be the most sensitive analogs, because their Co-A esters are substrates for CPT-I mediated transesterification prior to transport into the mitochondria [24].…”

“…To this end, efforts have been devoted to the development of fatty acid analogs radiolabeled with either 11 C (T 1/2 = 20.4 min) or 18 F (T 1/2 = 109.8 min), resulting in several agents that have shown promise [7][8][9][10]. 11 C-Palmitate (2, Figure 1) has been investigated A C C E P T E D M A N U S C R I P T…”