Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a ¹¹C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (CMTP, 1a). [¹¹C]CMTP ([¹¹C]1a) was synthesized by O-[¹¹C]methylation of desmethyl precursor 1b with [¹¹C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [¹¹C]CO₂) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [¹¹C]1a possessed moderate in vitro specific binding to mGluR2 in the rat brain, with a heterogeneous distribution of radioactive accumulation in the mGluR2-rich brain tissue sections, such as the cerebral cortex and striatum. PET study indicated that [¹¹C]1a was able to cross the blood–brain barrier and enter the brain, but had very low specific binding in the rat brain. Further optimization for the chemical structure of 1a is necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain.

在临床研究中，已证明选择性代谢型谷氨酸受体2（mGluR2）抑制剂可通过减轻精神分裂症患者的症状来显示治疗效果。本文中，我们报道了源自mGluR2抑制剂3-（环丙基甲基）-7-（（（4-（4-甲氧基苯基）哌啶-1-基）的¹¹ C标记正电子发射断层扫描（PET）示踪剂的合成和初步评估甲基）-8-（三氟甲基）-[1,2,4]三唑并[4,3- a ]吡啶（CMTP，1a）。[ ¹¹ C] CMTP（[ ¹¹ C] 1A）通过O-合成[ ¹¹的脱甲基前体C]甲基化1b中与[ ¹¹C]甲基碘的放射化学产率（基于[ ¹¹ C] CO ₂）为19.7±8.9％（n = 10），放射化学纯度> 98％，摩尔活性> 74 GBq /μmol。放射自显影研究表明[ ¹¹ C] 1a在大鼠脑中具有与mGluR2的适度体外特异性结合，并且在富含mGluR2的脑组织切片（如大脑皮层和纹状体）中放射性蓄积的分布不均。PET研究表明[ ¹¹ C] 1a能够穿过血脑屏障并进入大脑，但是在大鼠大脑中的特异性结合非常低。进一步优化1a的化学结构 必需增加与mGluR2的结合亲和力，然后改善体内脑中的特异性结合。