PURPOSE: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. PROCEDURES: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Alexandre Caron; Sébastien M Labbé; Sophie Carter; Marie-Claude Roy; Roger Lecomte; Daniel Ricquier; Frédéric Picard; Denis Richard Journal: Biochimie Date: 2017-01-24 Impact factor: 4.079
Authors: Denis P Blondin; Sébastien M Labbé; Christophe Noll; Margaret Kunach; Serge Phoenix; Brigitte Guérin; Éric E Turcotte; François Haman; Denis Richard; André C Carpentier Journal: Diabetes Date: 2015-02-12 Impact factor: 9.461