Synthesis and Preliminary Evaluation of an ¹⁸F-labeled Oleate Analog to Image Fatty Acid Beta-Oxidation in the...

Fatty acid oxidation (FAO) is a key parameter for evaluating cardiovascular, oncologic, neurologic, and other metabolic diseases. Several single-photon emission computed tomography and positron emission tomography (PET) tracers have been developed to measure FAO. Among these, 18-[¹⁸F]fluoro-4-thia-oleate ([¹⁸F]FTO), first developed by DeGrado et al., is well characterized. Here, we synthesized several analogs of [¹⁸F]FTO to improve the metabolic stability of the C-¹⁸F bond, and preliminarily evaluated their performance in monkey PET studies.

Several secondary ¹⁸F-fluorinated analogs, 17-[¹⁸F]fluoro-4-thia-oleate (17-[¹⁸F]FTO), 15-[¹⁸F]fluoro-4-thia-oleate (15-[¹⁸F]FTO), 12-[¹⁸F]fluoro-4-thia-oleate (12-[¹⁸F]FTO), 7-[¹⁸F]fluoro-4-thia-oleate, (7-[¹⁸F]FTO, [¹⁸F]AS3504073-00), and 6-[¹⁸F]fluoro-4-thia-oleate (6-[¹⁸F]FTO), were synthesized from tosylate or bromide precursors using similar procedures. Nucleophilic ¹⁸F fluorination on each precursor was performed using [¹⁸F]tetrabutylammonium fluoride/tetrabutylammonium hydrocarbonate, followed by hydrolysis of methylester. All synthesized ¹⁸F-labeled compounds were administered to cynomolgus monkeys, and PET measurements were performed. From the monkey PET studies, 7-[¹⁸F]FTO was selected as the best tracer and used to perform preliminary evaluations in mice.

All five compounds had sufficient quality and stability for animal experiments. In monkey PET studies, 12-, 7-, and 6-[¹⁸F]FTO showed greater accumulation in the heart than [¹⁸F]FTO, but not 17- and 15-[¹⁸F]FTO. Only 7-[¹⁸F]FTO did not show significant accumulation in the bone. The standardized uptake values (SUVs) for 12-[¹⁸F]FTO, 7-[¹⁸F]FTO, and 6-[¹⁸F]FTO were 9.77, 9.26, and 7.25 in the heart, and 3.17, n.d., and 1.96 in the bone 1 h after administration, respectively. In mouse distribution studies, SUVs 1 h after administration of 7-[¹⁸F]FTO and [¹⁸F]FTO were 10.4 and 10.0 in the heart, and 0.37 and 3.48 in the femur, respectively. Administration of etomoxir, a carnitine palmitoyltransferase inhibitor, reduced SUVs of 7-[¹⁸F]FTO and [¹⁸F]FTO in the heart by 91% and 87%, respectively.

We developed a novel PET tracer 7-[¹⁸F]FTO/[¹⁸F]AS3504073-00 for FAO imaging. 7-[¹⁸F]FTO had an excellent PET tracer profile, suggesting it may be a useful tracer for FAO imaging. Further evaluations of the tracer are ongoing.