Light Up Heart-type Fatty Acid Binding Protein (FABP3) with a Novel Fluorine-18 Labelled Selective FABP3 Ligand

Overview

Journal EJNMMI Res

Date 2024 Nov 14

PMID 39542944

Authors

Jun Toyohara

Taichi Komoda

Tetsuro Tago

Masahiko Ito

Hiroshi Yoshino

Affiliations

Soon will be listed here.

Abstract

Background: Heart-type fatty acid binding proteins (FABP3) constitute a family of lipid chaperone proteins. They are found in the cytosol and enhance cellular fatty acid solubilisation, transport, and metabolism. FABP3 is highly expressed in the myocardium and is released from myocytes during myocardial damage. As FABP3 content in the myocardium is closely related to the metabolic state of fatty acids, we hypothesised that targeting of FABP3 with a radiolabelled small organic compound would visualise myocardium.

Results: The selective FABP3 inhibitor, 4-(4-fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid (LUF), was radiolabelled via a two-step reaction comprising copper-mediated F-fluorination of an arylboronic precursor followed by alkaline hydrolysis of the ethoxy protecting group. [F]LUF was successfully synthesised by automated synthesiser with sufficient activity yields (14.0 ± 1.8 GBq) and high quality (molar activity, > 250 GBq/µmol and radiochemical purity, > 99.6%). Biological assessment of [F]LUF as an in vivo myocardial imaging agent included evaluations of biodistribution, metabolite analysis, and positron emission tomography (PET) imaging of small animals. [F]LUF clearly visualised the myocardium with high contrast against background tissues such as the lung and liver. [F]LUF also showed a high absolute myocardial uptake equivalent to that of the promising myocardial perfusion tracer [F]flurpiridaz and excellent metabolic stability in the body. These properties are ideal for stable and noise-less imaging of the heart. PET imaging of rat surgical permanent myocardial infarction (MI) and experimental autoimmune myocarditis (EAM) was also performed. [F]LUF successfully visualised lesions of permanent MI and EAM.

Conclusion: Our results showed for the first time that the F-labelled FABP3 selective small organic compound clearly visualised myocardium with good quality. To determine the clinical utility of [F]LUF for cardiovascular disease in clinical practice, it will be necessary to evaluate a greater variety of cardiovascular disease models and elucidate the accumulation mechanism, particularly in relation to fatty acid metabolism in the myocardium.

References

Burrell S, MacDonald A . Artifacts and pitfalls in myocardial perfusion imaging. J Nucl Med Technol. 2006; 34(4):193-211. View

Van Dongen A, van Rijk P . Minimizing liver, bowel, and gastric activity in myocardial perfusion SPECT. J Nucl Med. 2000; 41(8):1315-7. View

Guo Q, Kawahata I, Cheng A, Wang H, Jia W, Yoshino H . Fatty acid-binding proteins 3 and 5 are involved in the initiation of mitochondrial damage in ischemic neurons. Redox Biol. 2022; 59:102547. PMC: 9727700. DOI: 10.1016/j.redox.2022.102547. View

Binas B, Danneberg H, McWhir J, MULLINS L, Clark A . Requirement for the heart-type fatty acid binding protein in cardiac fatty acid utilization. FASEB J. 1999; 13(8):805-12. DOI: 10.1096/fasebj.13.8.805. View

Eryilmaz K, Kilbas B . A practical fully automated radiosynthesis of [F]Flurpiridaz on the module modular lab-pharmtracer without external purification. EJNMMI Radiopharm Chem. 2022; 7(1):30. PMC: 9637077. DOI: 10.1186/s41181-022-00182-z. View

DeGrado T, Bhattacharyya F, Pandey M, Belanger A, Wang S . Synthesis and preliminary evaluation of 18-(18)F-fluoro-4-thia-oleate as a PET probe of fatty acid oxidation. J Nucl Med. 2010; 51(8):1310-7. DOI: 10.2967/jnumed.109.074245. View

Garnier A, Poizat C, Keriel C, Cuchet P, Vork M, de Jong Y . Modulation of fatty acid-binding protein content of adult rat heart in response to chronic changes in plasma lipid levels. Mol Cell Biochem. 1993; 123(1-2):107-12. DOI: 10.1007/BF01076481. View

Tan L, Lu J, Liu L, Li L . Fatty acid binding protein 3 deficiency limits atherosclerosis development via macrophage foam cell formation inhibition. Exp Cell Res. 2021; 407(1):112768. DOI: 10.1016/j.yexcr.2021.112768. View

Renstrom B, Rommelfanger S, Stone C, DeGrado T, Carlson K, Scarbrough E . Comparison of fatty acid tracers FTHA and BMIPP during myocardial ischemia and hypoxia. J Nucl Med. 1998; 39(10):1684-9. View

10.

Otaki Y, Watanabe T, Kubota I . Heart-type fatty acid-binding protein in cardiovascular disease: A systemic review. Clin Chim Acta. 2017; 474:44-53. DOI: 10.1016/j.cca.2017.09.007. View

11.

Tamaki N, Morita K, Kawai Y . The Japanese experience with metabolic imaging in the clinical setting. J Nucl Cardiol. 2007; 14(3 Suppl):S145-52. DOI: 10.1016/j.nuclcard.2007.02.012. View

12.

Okabe T, Kishimoto C, Hattori M, Nimata M, Shioji K, Kita T . Cardioprotective effects of 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), a novel free radical scavenger, on acute autoimmune myocarditis in rats. Exp Clin Cardiol. 2009; 9(3):177-80. PMC: 2716743. View

13.

McKillop I, Girardi C, Thompson K . Role of fatty acid binding proteins (FABPs) in cancer development and progression. Cell Signal. 2019; 62:109336. DOI: 10.1016/j.cellsig.2019.06.001. View

14.

Alam L, Omar A, Patel K . Improved Performance of PET Myocardial Perfusion Imaging Compared to SPECT in the Evaluation of Suspected CAD. Curr Cardiol Rep. 2023; 25(4):281-293. DOI: 10.1007/s11886-023-01851-4. View

15.

Tsujimura E, Kusuoka H, Fukuchi K, Hasegawa S, Yutani K, Hori M . Changes in perfusion and fatty acid metabolism of rat heart with autoimmune myocarditis. Ann Nucl Med. 2000; 14(5):361-7. DOI: 10.1007/BF02988696. View

16.

Savisto N, Viljanen T, Kokkomaki E, Bergman J, Solin O . Automated production of [ F]FTHA according to GMP. J Labelled Comp Radiopharm. 2017; 61(2):84-93. DOI: 10.1002/jlcr.3589. View

17.

DeGrado T, Wang S, Holden J, Nickles R, Taylor M, Stone C . Synthesis and preliminary evaluation of (18)F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation. Nucl Med Biol. 2000; 27(3):221-31. DOI: 10.1016/s0969-8051(99)00101-8. View

18.

Harada N, Nishiyama S, Kanazawa M, Tsukada H . Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain. J Labelled Comp Radiopharm. 2013; 56(11):553-61. DOI: 10.1002/jlcr.3056. View

19.

Toyohara J, Nishino K, Sakai M, Tago T, Oda T . Automated production of [F]MK-6240 on CFN-MPS200. Appl Radiat Isot. 2020; 168:109468. DOI: 10.1016/j.apradiso.2020.109468. View

20.

Ustsinau U, Nics L, Hacker M, Philippe C . A Fully Automated Synthesis of 14-()-[F]fluoro-6-thia-heptadecanoic Acid ([F]FTHA) on the Elixys Radiosynthesizer. Pharmaceuticals (Basel). 2024; 17(3). PMC: 10975787. DOI: 10.3390/ph17030318. View