3-(Cyclopropylmethyl)-7-((4-(4-[11C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2
3-(Cyclopropylmethyl)-7-((4-(4-[11C]methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine: Synthesis and preliminary evaluation for PET imaging of metabotropic glutamate receptor subtype 2
复制标题
3-(环丙基甲基)-7-((4-(4-[11C]甲氧基苯基)哌啶-1-基)甲基)-8-(三氟甲基)-[1,2,4]三唑并[4,3-a]
DOI：
10.1016/j.bmcl.2020.127555
复制
发表时间：
2020
影响因子：
2.7
通讯作者：
Zhang Ming-Rong
中科院分区：
文献类型：
--
作者：
Kumata Katsushi;Zhang Yiding;Ogawa Masanao;Kurihara Yusuke;Mori Wakana;Hu Kuan;Fujinaga Masayuki;Nengaki Nobuki;Zhang Ming-Rong
选择性代谢型谷氨酸受体2 （mGluR2）抑制剂在临床研究中显示出改善缓解精神分裂症患者症状的治疗效果。本文报道了以mGluR2抑制剂3-（环丙基甲基）-7-(（4-（4-甲氧基苯基）哌啶-1-基）甲基-8-（三氟甲基）-[1,2,4]三唑[4,3-a]吡啶（CMTP,1a）为原料的a11c标记正电子发射断层扫描（PET）示踪剂的合成和初步评价。用[11C]碘化甲基化去甲基前体1b合成[11C]CMTP ([11C]1a)，放射化学产率（基于[11C]CO2）为19.7±8.9% (n = 10)，放射化学纯度为>98%，活性为bbb74 GBq/μmol。放射自显影研究表明[11C]1在大鼠脑中与mGluR2具有适度的体外特异性结合，在富含mGluR2的脑组织切片，如大脑皮层和纹状体中具有非均匀分布的放射性积累。PET研究表明[11C]1能够穿过血脑屏障进入大脑，但在大鼠脑中的特异性结合非常低。为了提高与mGluR2的结合亲和力，进而提高脑内特异性结合，需要进一步优化1的化学结构。
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 a11C-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 precursor1bwith [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]1apossessed 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]1awas 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 of1ais necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain.