Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, Massachusetts 02114, United States.
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
J Med Chem. 2021 Oct 14;64(19):14283-14298. doi: 10.1021/acs.jmedchem.1c00747. Epub 2021 Sep 27.
Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds and were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [F] and [F] ([F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [F] demonstrated a better performance. In conclusion, [F] was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans.
单酰甘油脂肪酶（MAGL）是一种 33kDa 的丝氨酸蛋白酶，主要负责水解 2-花生四烯酰甘油，在中枢神经系统中生成促炎类二十烷酸前体花生四烯酸。抑制 MAGL 构成了治疗精神疾病和神经退行性疾病的有吸引力的治疗概念。在此，我们基于哌嗪基氮杂环丁烷骨架设计并合成了多种可还原的 MAGL 抑制剂候选物。通过药理学评估，化合物 和 被鉴定为表现最佳的可还原 MAGL 抑制剂，因此能够以高放射化学产率和有利的摩尔活性对其进行氟-18 标记。此外，通过放射性自显影和正电子发射断层扫描（PET）成像在啮齿动物和非人灵长类动物中对 [F] 和 [F]（[F]MAGL-2102）进行评估，显示出有利的脑摄取、不均匀的放射性分布、良好的特异性结合和足够的脑动力学，并且 [F] 表现出更好的性能。总之，发现 [F] 是一种适合用于可视化 MAGL 的 PET 放射性配体，具有成功转化为人类的潜力。
