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Synthesis and Preliminary Evaluation of an 18F-labeled Oleate Analog to Image Fatty Acid Beta-Oxidation in the Absence of Metabolic Defluorination

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A Correction to this article was published on 15 November 2022

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Abstract

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.

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References

  1. Fillmore N, Mori J, Lopaschuk GD (2014) Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol 171:2080–2090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fukushima A, Lopaschuk GD (2016) Acetylation control of cardiac fatty acid beta-oxidation and energy metabolism in obesity, diabetes, and heart failure. Biochim Biophys Acta 1862:2211–2220

    Article  CAS  PubMed  Google Scholar 

  3. Wang J, Xiang H, Lu Y (2021) The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression. Am J Cancer Res 11:2477–2494

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tein I (2013) Disorders of fatty acid oxidation. Handb Clin Neurol 113:1675–1688

    Article  PubMed  Google Scholar 

  5. Fucho R, Casals N, Serra D (2017) Ceramides and mitochondrial fatty acid oxidation in obesity. FASEB J 31:1263–1272

    Article  CAS  PubMed  Google Scholar 

  6. Mather KJ, DeGrado TR (2016) Imaging of myocardial fatty acid oxidation. Biochim Biophys Acta 1861:1535–1543

    Article  CAS  PubMed  Google Scholar 

  7. Giedd KN, Bergmann SR (2011) Fatty acid imaging of the heart. Curr Cardiol Rep 13:121–131

    Article  PubMed  Google Scholar 

  8. Caron A, Labbe SM, Carter S (2017) Loss of UCP2 impairs cold-induced non-shivering thermogenesis by promoting a shift toward glucose utilization in brown adipose tissue. Biochimie 134:118–126

    Article  CAS  PubMed  Google Scholar 

  9. Blondin DP, Labbe SM, Noll C (2015) Selective impairment of glucose but not fatty acid or oxidative metabolism in brown adipose tissue of subjects with type 2 diabetes. Diabetes 64:2388–2397

    Article  CAS  PubMed  Google Scholar 

  10. Tamaki N, Yoshinaga K (2011) Novel iodinated tracers, MIBG and BMIPP, for nuclear cardiology. J Nucl Cardiol 18:135–143

    Article  PubMed  Google Scholar 

  11. DeGrado TR, Coenen HH, Stocklin G (1991) 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA): evaluation in mouse of a new probe of myocardial utilization of long chain fatty acids. J Nucl Med 32:1888–1896

    CAS  PubMed  Google Scholar 

  12. DeGrado TR, Wang S, Holden JE (2000) Synthesis and preliminary evaluation of 18F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation. Nucl Med Biol 27:221–231

    Article  CAS  PubMed  Google Scholar 

  13. DeGrado TR, Bhattacharyya F, Pandey MK (2010) Synthesis and preliminary evaluation of 18–18F-fluoro-4-thia-oleate as a PET probe of fatty acid oxidation. J Nucl Med 51:1310–1317

    Article  CAS  PubMed  Google Scholar 

  14. Cai Z, Mason NS, Anderson CJ (2016) Synthesis and preliminary evaluation of an 18F-labeled oleic acid analog for PET imaging of fatty acid uptake and metabolism. Nucl Med Biology 43:108–115

    Article  CAS  Google Scholar 

  15. Kim DH, Choe YS, Choi JY (2009) 17-[4-(2-[18F]fluoroethyl)-1H-1,2,3-triazol-1-yl]-6-thia-heptadecanoic acid: a potential radiotracer for the evaluation of myocardial fatty acid metabolism. Bioconjug Chem 20:1139–1145

    Article  CAS  PubMed  Google Scholar 

  16. Shoup TM, Elmaleh DR, Bonab AA (2005) Evaluation of trans-9-18F-fluoro-3,4-methyleneheptadecanoic acid as a PET tracer for myocardial fatty acid imaging. J Nucl Med 46:297–304

    CAS  PubMed  Google Scholar 

  17. Takahashi T, Nishimura S, Ido T (1996) Biological evaluation of 5-methyl-branched-chain omega-[18F]fluorofatty acid: a potential myocardial imaging tracer for positron emission tomography. Nucl Med Biol 23:303–308

    Article  CAS  PubMed  Google Scholar 

  18. Ebert A, Herzog H, Stocklin GL (1994) Kinetics of 14(R, S)-fluorine-18-fluoro-6-thia-heptadecanoic acid in normal human hearts at rest, during exercise and after dipyridamole injection. J Nucl Med 35:51–56

    CAS  PubMed  Google Scholar 

  19. Takala TO, Nuutila P, Pulkki K (2002) 14(R, S)-[18F]Fluoro-6-thia-heptadecanoic acid as a tracer of free fatty acid uptake and oxidation in myocardium and skeletal muscle. Eur J Nucl Med Mol Imaging 29:1617–1622

    Article  CAS  PubMed  Google Scholar 

  20. DeGrado TR, Kitapci MT, Wang S (2006) Validation of 18F-fluoro-4-thia-palmitate as a PET probe for myocardial fatty acid oxidation: effects of hypoxia and composition of exogenous fatty acids. J Nucl Med 47:173–181

    CAS  PubMed  Google Scholar 

  21. Campbell DO, Noda A, Verlinsky A (2016) Preclinical evaluation of an anti-nectin-4 immunopet reagent in tumor-bearing mice and biodistribution studies in cynomolgus monkeys. Mol Imaging Biol 18:768–775

    Article  CAS  PubMed  Google Scholar 

  22. Kam W, Kumaran K, Landau BR (1978) Contribution of omega-oxidation to fatty acid oxidation by liver of rat and monkey. J Lipid Res 19:591–600

    Article  CAS  PubMed  Google Scholar 

  23. Adas F, Berthou F, Picart D, Lozac’h P, Beaugé F, Amet Y (1998) Involvement of cytochrome P450 2E1 in the (omega-1)-hydroxylation of oleic acid in human and rat liver microsomes. J. Lipid Res. 39:1210–1219

    Article  CAS  PubMed  Google Scholar 

  24. Adas F, Berthou F, Salaün JP, Dréano Y, Amet Y (1999) Interspecies variations in fatty acid hydroxylations involving cytochromes P450 2E1 and 4A. Toxicol Lett 110:43–55

    Article  CAS  PubMed  Google Scholar 

  25. Kim KR, Oh DK (2013) Production of hydroxy fatty acids by microbial fatty acid-hydroxylation enzymes Biotechnol. Adv 31:1473–1485

    CAS  Google Scholar 

  26. Abdurrachim D, Nabben M, Hoerr V (2017) Diabetic db/db mice do not develop heart failure upon pressure overload: a longitudinal in vivo PET, MRI, and MRS study on cardiac metabolic, structural, and functional adaptations. Cardiovasc Res 113:1148–1160

    Article  CAS  PubMed  Google Scholar 

  27. Hosokawa R, Nohara R, Fujibayashi Y (1996) Metabolic fate of iodine-123-BMIPP in canine myocardium after administration of etomoxir. J Nucl Med 37:1836–1840

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors wish to thank Drs. Takahiro Higuchi, Yoshiteru Kamiyama, and Takashi Nozawa for discussions; and Toshikazu Kangoori, Hidetoshi Takada, Tomoyasu Shinzawa, and Jun Nagase for their technical assistance.

Funding

This study funded by Astellas Pharma Inc. [18F]AS3504073-00 is issued by WO2020017620.

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Authors and Affiliations

  1. Astellas Pharma, Inc, 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan

    Yoshihiro Murakami, Yuji Fujita & Hiroshi Fushiki

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  1. Yoshihiro Murakami
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  2. Yuji Fujita
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  3. Hiroshi Fushiki
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Corresponding author

Correspondence to Hiroshi Fushiki.

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Ethics Approval

All animal experiment procedures were approved by the Committee for Animal Experiments of Astellas Pharma Inc., which was awarded Accreditation Status by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International.

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All authors are employees of Astellas Pharma, Inc.

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Murakami, Y., Fujita, Y. & Fushiki, H. Synthesis and Preliminary Evaluation of an 18F-labeled Oleate Analog to Image Fatty Acid Beta-Oxidation in the Absence of Metabolic Defluorination. Mol Imaging Biol 25, 495–502 (2023). https://doi.org/10.1007/s11307-022-01777-3

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