Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan; SHI Accelerator Service Co., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
Bioorg Med Chem. 2019 Aug 15;27(16):3568-3573. doi: 10.1016/j.bmc.2019.06.037. Epub 2019 Jun 29.
Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, the inhibition of MAGL is an attractive therapeutic target for neurodegenerative diseases. In this study, to visualize MAGL via positron emission tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1H-pyrazol-3-yl)azetidine-1-[C]carboxylate ([C]6). Compound 6 exhibited high in vitro binding affinity (IC = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [C]6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [C]phosgene ([C]COCl), followed by a reaction with 3-(1-benzyl-1H-pyrazol-3-yl)azetidine hydrochloride (8), which resulted in a 15.0 ± 6.8% radiochemical yield (decay-corrected, n = 7) based on [C]CO and a 45 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in MAGL-rich organs, including the lungs, heart, and kidneys. More than 90% of the total radioactivity was irreversibly bound in the brain homogenate of rats 5 min and 30 min after the radiotracer injection. PET summation images of rat brains showed high radioactivity in all brain regions. Pretreatment with 6 or MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. [C]6 is a promising PET tracer which offers in vivo specific binding and selectivity for MAGL in rodent brains.
单酰基甘油脂肪酶（MAGL）是一种主要的丝氨酸水解酶，可将 2-花生四烯酰甘油（2-AG）水解为大脑中的花生四烯酸（AA）和甘油。因为 2-AG 和 AA 是大脑中内源性生物活性配体，所以 MAGL 的抑制作用是神经退行性疾病的一个有吸引力的治疗靶点。在这项研究中，为了通过正电子发射断层扫描（PET）可视化 MAGL，我们报告了一种新的碳-11 标记放射性示踪剂，即 1,1,1,3,3,3-六氟-2-丙醇-3-（1-苄基-1H-吡唑-3-基）氮杂环丁烷-1-[C]羧酸酯（[C]6）。化合物 6 在大脑中表现出对 MAGL 的高体外结合亲和力（IC = 0.41 nM），具有合适的亲脂性（cLogD = 3.29）。[C]6 通过反应 1,1,1,3,3,3-六氟-1-丙醇（7）与[C]光气（[C]COCl），然后与 3-（1-苄基-1H-吡唑-3-基）氮杂环丁烷盐酸盐（8）反应，导致基于[C]CO 的放射性化学产率为 15.0 ± 6.8%（decay-corrected，n = 7），从轰击结束到合成结束的时间为 45 分钟。在小鼠中的生物分布研究表明，放射性示踪剂在富含 MAGL 的器官中具有高摄取率，包括肺、心脏和肾脏。在大鼠放射性示踪剂注射后 5 分钟和 30 分钟，脑匀浆中超过 90%的总放射性活性不可逆结合。大鼠脑的 PET 总和图像显示所有脑区均有高放射性活性。用 6 或 MAGL 选择性抑制剂 JW642 预处理可显著降低脑内放射性示踪剂的摄取。[C]6 是一种很有前途的 PET 示踪剂，可在啮齿动物大脑中提供 MAGL 的体内特异性结合和选择性。
