TY - JOUR
T1 - Synthesis and preliminary evaluation of 18-18F-fluoro-4-thia- oleate as a PET probe of fatty acid oxidation
AU - DeGrado, Timothy R.
AU - Bhattacharyya, Falguni
AU - Pandey, Mukesh K.
AU - Belanger, Anthony P.
AU - Wang, Shuyan
PY - 2010/8
Y1 - 2010/8
N2 - 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, 18-18F-fluoro-4-thia-oleate (18F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-18F-fluoro-4-thia-palmitate (18F-FTP) as an FAO probe. Methods: 18F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with 18F-FTO and 18F-FTP in rats. Results: A practical synthesis of 18F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of 18F-FTO (0.70 ± 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of 18F-FTP at 30 min after injection. At 2 h, myocardial uptake of 18F-FTO was maintained, whereas 18F-FTP uptake in the heart was 82% reduced. Similar to 18F-FTP, 18F-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 18F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of 18F-FTO and of 18F-FTP into the heart and liver. Images of 18F-FTO accumulation in the rat myocardium were clearly superior to those of 18F-FTP. Conclusion: 18F-FTO is shown to be a promising metabolically trapped FAO. probe that warrants further evaluation.
AB - 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, 18-18F-fluoro-4-thia-oleate (18F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-18F-fluoro-4-thia-palmitate (18F-FTP) as an FAO probe. Methods: 18F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with 18F-FTO and 18F-FTP in rats. Results: A practical synthesis of 18F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of 18F-FTO (0.70 ± 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of 18F-FTP at 30 min after injection. At 2 h, myocardial uptake of 18F-FTO was maintained, whereas 18F-FTP uptake in the heart was 82% reduced. Similar to 18F-FTP, 18F-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 18F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of 18F-FTO and of 18F-FTP into the heart and liver. Images of 18F-FTO accumulation in the rat myocardium were clearly superior to those of 18F-FTP. Conclusion: 18F-FTO is shown to be a promising metabolically trapped FAO. probe that warrants further evaluation.
KW - Fatty acid oxidation
KW - Myocardial metabolism
KW - PET
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U2 - 10.2967/jnumed.109.074245
DO - 10.2967/jnumed.109.074245
M3 - Article
C2 - 20660391
AN - SCOPUS:77956196117
SN - 0161-5505
VL - 51
SP - 1310
EP - 1317
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 8
ER -