Metabotropic glutamate receptor 2 (mGlu₂) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu₂, we identified new candidates 5a–i that are potent negative allosteric modulators (NAMs) of mGlu₂. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [¹¹C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (¹¹C) to obtain [¹¹C]5i in high radiochemical yield and high molar activity by O-[¹¹C]methylation of the phenol precursor 12 with [¹¹C]CH₃I. In vitro autoradiography with [¹¹C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [¹¹C]5i indicated in vivo specific binding of mGlu₂ in the rat brain. Based on the [¹¹C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu₂.

中文翻译：

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用于成像代谢型谷氨酸受体亚型的新型正电子发射断层扫描配体 4-(2-氟-4-[11C]甲氧基苯基)-5-((1-甲基-1H-吡唑-3-基)甲氧基)吡啶甲酰胺的鉴定和开发2 (mGlu2)。

代谢型谷氨酸受体 2 (mGlu ₂ ) 是治疗多种中枢神经系统 (CNS) 疾病的已知靶点。为了为 mGlu ₂开发可行的正电子发射断层扫描 (PET) 配体，我们确定了新的候选物5a – i，它们是 mGlu _{2 的}有效负变构调节剂 (NAM) 。在这些候选物中，4-(2-氟-4-甲氧基苯基)-5-((1-甲基-1H-吡唑-3-基)甲氧基)吡啶甲酰胺( 5i，也称为[ ¹¹ C]MG2-1812)表现出高效力、高亚型选择性和良好的亲脂性。化合物5i用正电子发射碳11 ( ¹¹ C)标记得到[¹¹ C] 5i具有高放射化学产率和高摩尔活性，通过苯酚前体12与 [ ¹¹ C]CH ₃ I的O -[ ¹¹ C] 甲基化。[ ¹¹ C] 5i 的体外放射自显影显示大脑中的异质放射性积累组织切片，按顺序排列：皮质>纹状体>海马>小脑≫丘脑>脑桥。[ ¹¹ C] 5i 的PET 研究表明mGlu ₂在大鼠脑中的体内特异性结合。基于[ ¹¹ C] 5i支架上，正在对新候选物进行进一步优化，以确定更适合 mGlu 成像的配体₂。