Radiolabeling and Preclinical Evaluation of 2-[¹⁸F]Fluorohexanoic Acid: A Novel Medium-Chain Fatty Acid Metabolism Tracer for PET Imaging of Tumors

Fatty acid metabolism plays a critical role in cancer development. In this study, a novel medium-chain fatty acid (MCFA) PET tracer, 2-[¹⁸F]fluorohexanoic acid (¹⁸F-FHA), was successfully synthesized with high radiochemical yield (65 ± 5.4%) and purity (>99%). Tumor radiotracer uptake at 60 min in A431, Hek293, Kpc, 4T1, Hep3b, and Lm3 xenograft models was 7.1 ± 0.4, 8.8 ± 0.6, 7.7 ± 0.5, 7.2 ± 0.4, 5.1 ± 0.3, and 4.9 ± 0.3 percentage injected dose per gram (% ID/g), respectively. Pretreatment with salicylic acid (SA), an inhibitor of medium-chain acyl-CoA synthetase (ACSM), significantly enhanced tumor uptake (<i>p</i> < 0.05) but showed no effect on blood uptake (<i>p</i> = 0.115). The biodistribution analysis demonstrated that ¹⁸F-FHA exhibited rapid hepatic and cardiac accumulation followed by gradual clearance, whereas tumor uptake exhibited gradual elevation within the initial 20 min and remained relatively stable through the 90 min observation period. ¹⁸F-FHA warranted further investigation as a potential PET imaging agent for tumors.