Toyohara Jun, Komoda Taichi, Tago Tetsuro, Ito Masahiko, Yoshino Hiroshi
Research Team for Neuroimaging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
R&D Center, Shiratori Pharmaceuticals Co., Ltd., Narashino, Japan.
EJNMMI Res. 2024 Nov 14;14(1):107. doi: 10.1186/s13550-024-01175-6.
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.
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.
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.
心脏型脂肪酸结合蛋白（FABP3）构成了一类脂质伴侣蛋白家族。它们存在于细胞质中，可增强细胞内脂肪酸的溶解、转运及代谢。FABP3在心肌中高度表达，在心肌损伤时从心肌细胞中释放出来。由于心肌中FABP3的含量与脂肪酸的代谢状态密切相关，我们推测用放射性标记的小分子有机化合物靶向FABP3可使心肌显影。
选择性FABP3抑制剂4-(4-氟-2-(1-苯基-5-(2-(三氟甲基)苯基)-1H-吡唑-3-基)苯氧基)丁酸（LUF）通过两步反应进行放射性标记，第一步是铜介导的芳基硼酸前体的F-氟化反应，第二步是乙氧基保护基团的碱性水解反应。[F]LUF通过自动合成仪成功合成，具有足够的活度产率（14.0±1.8 GBq）和高质量（摩尔活度>250 GBq/µmol，放射化学纯度>99.6%）。对[F]LUF作为体内心肌显像剂的生物学评估包括生物分布、代谢物分析以及小动物正电子发射断层扫描（PET）成像。[F]LUF能清晰地使心肌显影，与肺和肝脏等背景组织形成高对比度。[F]LUF还显示出与有前景的心肌灌注示踪剂[F]氟吡哒唑相当的高绝对心肌摄取量以及在体内出色的代谢稳定性。这些特性对于心脏的稳定且无噪声成像非常理想。还对大鼠手术性永久性心肌梗死（MI）和实验性自身免疫性心肌炎（EAM）进行了PET成像。[F]LUF成功地使永久性MI和EAM的病变显影。
我们的结果首次表明，F标记的FABP3选择性小分子有机化合物能清晰地使心肌显影，质量良好。为了确定[F]LUF在临床实践中对心血管疾病的临床应用价值，有必要评估更多种类的心血管疾病模型，并阐明其蓄积机制，特别是与心肌脂肪酸代谢有关的机制。
