Synthesis and preliminary evaluation of 18-(18)F-fluoro-4-thia-oleate as a PET probe of fatty acid oxidation.
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-(18)F-fluoro-4-thia-oleate ((18)F-FTO), was evaluated in relationship to the previously developed palmitate analog 16-(18)F-fluoro-4-thia-palmitate ((18)F-FTP) as an FAO probe.


METHODS
(18)F-FTO was synthesized from a corresponding bromoester. Biodistribution and metabolite analysis studies were performed in rats. Preliminary small-animal PET studies were performed with (18)F-FTO and (18)F-FTP in rats.


RESULTS
A practical synthesis of (18)F-FTO was developed, providing a radiotracer of high radiochemical purity (>99%). In fasted rats, myocardial uptake of (18)F-FTO (0.70 +/- 0.30% dose kg [body mass]/g [tissue mass]) was similar to that of (18)F-FTP at 30 min after injection. At 2 h, myocardial uptake of (18)F-FTO was maintained, whereas (18)F-FTP uptake in the heart was 82% reduced. Similar to (18)F-FTP, (18)F-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 (18)F-FTO to the mitochondrion with subsequent metabolism to protein-bound species. Preliminary small-animal PET studies showed rapid blood clearance and avid extraction of (18)F-FTO and of (18)F-FTP into the heart and liver. Images of (18)F-FTO accumulation in the rat myocardium were clearly superior to those of (18)F-FTP.


CONCLUSIONS
(18)F-FTO is shown to be a promising metabolically trapped FAO probe that warrants further evaluation.
DeGrado
Timothy R
TR
Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. tdegrado@partners.org
Bhattacharyya
Falguni
F
Pandey
Mukesh K
MK
Belanger
Anthony P
AP
Wang
Shuyan
S
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging; D009206:Myocardium / Q000378:metabolism; D009829:Oleic Acids / Q000138:chemical synthesis*; D010084:Oxidation-Reduction; D010168:Palmitates; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000138:chemical synthesis*; D013871:Thiones; D014018:Tissue Distribution
C515150:16-fluoro-4-thiapalmitic acid; C551790:18-fluoro-4-thiaoleic acid; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D009829:Oleic Acids; D010168:Palmitates; D019275:Radiopharmaceuticals; D013440:Sulfides; D013871:Thiones; C054207:etomoxir