Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan; SHI Accelerator Service, Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
Bioorg Med Chem Lett. 2020 Dec 1;30(23):127555. doi: 10.1016/j.bmcl.2020.127555. Epub 2020 Sep 15.
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 C-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). [C]CMTP ([C]1a) was synthesized by O-[C]methylation of desmethyl precursor 1b with [C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [C]CO) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [C]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 [C]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.
选择性代谢型谷氨酸受体 2（mGluR2）抑制剂已在临床研究中被证明通过改善精神分裂症患者的症状具有治疗作用。在此，我们报告了一种源自 mGluR2 抑制剂的 C 标记正电子发射断层扫描（PET）示踪剂的合成和初步评价，该抑制剂为 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]三唑并[4,3-a]吡啶（CMTP，1a）。[C]CMTP（[C]1a）是通过用[C]甲基碘对去甲前体 1b 的 O-[C]甲基化在 19.7±8.9%（n=10）放射性化学产率（基于[C]CO）下合成的，具有 >98%的放射性化学纯度和 >74GBq/μmol 摩尔活性。放射自显影研究表明，[C]1a 在大鼠脑中具有中等的体外特异性结合 mGluR2，放射性积聚在 mGluR2 丰富的脑组织切片中具有不均匀的分布，如大脑皮层和纹状体。PET 研究表明，[C]1a 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。需要进一步优化 1a 的化学结构，以增加对 mGluR2 的结合亲和力，从而提高脑内的特异性结合。
