Synthesis and preliminary evaluation of 18-18F-fluoro-4-thia- oleate as a PET probe of fatty acid oxidation

Timothy R DeGrado, Falguni Bhattacharyya, Mukesh Pandey, Anthony P. Belanger, Shuyan Wang

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1310-1317
Number of pages8
JournalJournal of Nuclear Medicine
Volume51
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

Fingerprint

Oleic Acid
Fatty Acids
Palmitates
Myocardium
18-fluoro-4-thiaoleic acid
Liver
Metabolic Diseases
Nervous System Diseases
Mitochondria
Skeletal Muscle
Proteins
Cardiovascular Diseases
Injections

Keywords

  • Fatty acid oxidation
  • Myocardial metabolism
  • PET

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Medicine(all)

Cite this

Synthesis and preliminary evaluation of 18-18F-fluoro-4-thia- oleate as a PET probe of fatty acid oxidation. / DeGrado, Timothy R; Bhattacharyya, Falguni; Pandey, Mukesh; Belanger, Anthony P.; Wang, Shuyan.

In: Journal of Nuclear Medicine, Vol. 51, No. 8, 08.2010, p. 1310-1317.

Research output: Contribution to journalArticle

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abstract = "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.",
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T1 - Synthesis and preliminary evaluation of 18-18F-fluoro-4-thia- oleate as a PET probe of fatty acid oxidation

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AU - Bhattacharyya, Falguni

AU - Pandey, Mukesh

AU - Belanger, Anthony P.

AU - Wang, Shuyan

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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.

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