Synthesis and Preliminary Evaluation of Metabolically Stable ¹⁸F-Lableled PET Tracer for Fatty Acid Beta-Oxidation Imaging.

Introduction: Evaluation of fatty acid oxidation is one of the key information for cardiovascular, oncologic, neurologic, and other metabolic diseases. Some SPECT and PET tracers have been developed to measure beta-oxidation, and 18-[¹⁸F]fluoro-4-thia-oleate ([¹⁸F]FTO) was reported as a PET tracer developed by DeGrado et al. However, the accumulation of radioactivity in bone was also observed by defluorination. In the present study, several analogs of [¹⁸F]FTO were synthesized to improve the metabolic stability of C-¹⁸F bond, and were preliminarily evaluated in monkey PET studies.

Methods: Three secondary fluorinated analogs, 17-fluoro-4-thia-oleate (17-FTO), 15-fluoro-4-thia-oleate (15-FTO), and 7-fluoro-4-thia-oleate, (7-FTO, AS3504073-00) were designed based on FTO as a lead compound and performed ¹⁸F-labeled synthesis. All ¹⁸F-labeled compounds were prepared using a two-step synthesis which were (i) a nucleophilic ¹⁸F fluorination on a tosylate-precursor, and (ii) a hydrolysis of methylester. Product purification was done by semi-prep HPLC, followed by solid phase extraction eluted with ethanol and saline dilution including ascorbic acid. The obtained ¹⁸F-labeled tracers were administered to cynomolgus monkeys and PET measurements were performed.

Results: All three compounds were successfully synthesized with enough quality and stability for animal experiment in a similar manner. In monkey PET studies, 17-[¹⁸F]FTO and 15-[¹⁸F]FTO were decreased in the bone accumulation, but not changed in the heart in comparison with [¹⁸F]FTO. Surprisingly, only [¹⁸F]AS3504073-00 showed much more uptake in the heart than that of [¹⁸F]FTO and no significant accumulation of radioactivity was observed in the bone. The SUV value of [¹⁸F]AS3504073-00 was 8.46, 9.26 and 8.85 in the heart at 20, 60 and 120 min after administration, respectively.

Conclusions: In the present study, we developed a novel PET tracer [¹⁸F]AS3504073-00 for beta-oxidation imaging. [¹⁸F]AS3504073-00 showed excellent profile as a PET tracer, so that [¹⁸F]AS3504073-00 seemed to be one of the best tracers for beta-oxidation imaging. Further evaluations are ongoing.

• Download figure
• Open in new tab
• Download powerpoint