Monoacylglycerol lipase (MAGL) is a gatekeeper in regulating endocannabinoid signaling and has gained substantial attention as a therapeutic target for neurological disorders. We recently discovered a morpholin-3-one derivative as a novel scaffold for imaging MAGL via positron emission tomography (PET). However, its slow kinetics in vivo hampered the application. In this study, structural optimization was conducted and eleven novel MAGL inhibitors were designed and synthesized. Based on the results from MAGL inhibitory potency, in vitro metabolic stability and surface plasmon resonance assays, we identified compound 7 as a potential MAGL PET tracer candidate. [¹¹C]7 was synthesized via direct ¹¹CO₂ fixation method and successfully mapped MAGL distribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [¹¹C]7 demonstrated its improved kinetic profile compared to the lead structure. Its high specificity in vivo was proved by using MAGL KO mice. Although further studies confirmed that [¹¹C]7 is a P-glycoprotein (P-gp) substrate in mice, its low P-gp efflux ratio on cells transfected with human protein suggests that it should not be an issue for the clinical translation of [¹¹C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [¹¹C]7 ([¹¹C]RO7284390) showed promising results warranting further clinical evaluation.

单酰基甘油脂肪酶 (MAGL) 是调节内源性大麻素信号传导的看门人，作为神经系统疾病的治疗靶点已引起广泛关注。我们最近发现了一种 morpholin-3-one 衍生物作为一种新型支架，用于通过正电子发射断层扫描 (PET)对 MAGL 进行成像。然而，其在体内的缓慢动力学阻碍了其应用。在这项研究中，进行了结构优化，设计并合成了 11 种新型 MAGL 抑制剂。基于 MAGL 抑制效力、体外代谢稳定性和表面等离子共振测定的结果，我们将化合物7鉴定为潜在的 MAGL PET 示踪剂候选物。[ ¹¹ C] 7被合成通过直接¹¹ CO _{2固定方法并}在体外放射自显影中成功绘制了啮齿动物大脑上的 MAGL 分布模式。^{使用[ 11} C] 7对小鼠进行的PET研究表明，与铅结构相比，它的动力学曲线有所改善。使用 MAGL KO 小鼠证明了其在体内的高特异性。尽管进一步的研究证实 [ ¹¹ C] 7是小鼠体内的 P-糖蛋白 (P-gp) 底物，但其在转染人蛋白的细胞上的低 P-gp 流出率表明它不应该成为临床转化的问题。 [ ¹¹ C] 7作为一种新颖的可逆 MAGL PET 示踪剂在人类受试者中。总体而言，[ ¹¹ C] 7 ([ ¹¹ C]RO7284390) 显示出有希望的结果，值得进一步临床评估。