Leung Kam
National Center for Biotechnology Information, NLM, NIH
Glutamate is a major excitatory neurotransmitter at neuronal synapses in the central nervous system (CNS) (1, 2). Glutamate produces excitatory effects by acting on cell-surface ionotropic glutamate or metabotropic glutamate receptors (mGluRs). The mGluRs are GTP-binding protein (G-protein)–coupled receptors that play important roles in regulating the activity of many synapses in the CNS, and many neuronal projection pathways contain mGluRs. There are eight mGluR subtypes, which are further subdivided into groups I, II, and III. The group I receptors include mGluR1 and mGluR5, and they are found predominantly in postsynaptic locations. mGluR1 is found in moderate to high density in the cerebellum, caudate, putamen, thalamus, cingulate cortex, and hippocampus, with low density in the pons. mGluR5 is usually found in moderate to high density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, and hippocampus, with low density in the cerebellum. mGluR1 and mGluR5 are positively coupled to phospholipase C in the regulation of neuronal excitability (3). Dysfunction of mGluR1 and mGluR5 is implicated in a variety of diseases in the CNS, including anxiety, depression, schizophrenia, Parkinson’s disease, and drug addiction or withdrawal (2, 4). Positron emission tomography (PET) radioligands targeting mGluR5 can visualize and analyze mGluR5 expression in normal physiological and pathological conditions (4-8). However, only a few mGluR1 ligands have been studied. -(4-(6-(Isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy--methylbenzamide (ITMM) was shown to be a selective mGluR1 antagonist with nanomolar affinity ( = 12.6 nM), with little inhibition of mGluR5. Fujinaga et al. (9) labeled ITMM with C to prepare -(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[C]methoxy--methylbenzamide ([C]ITMM) for use with PET imaging of mGluR1 distribution in rat brains. Toyohara et al. (10) evaluated [C]ITMM in mouse and human brains. [C]ITMM was shown to be a suitable PET radioligand for mapping mGluR1 in the human brain.
谷氨酸是中枢神经系统（CNS）神经元突触中的主要兴奋性神经递质（1,2）。谷氨酸通过作用于细胞表面离子型谷氨酸受体或代谢型谷氨酸受体（mGluRs）产生兴奋作用。mGluRs是鸟苷三磷酸结合蛋白（G蛋白）偶联受体，在调节CNS中许多突触的活性方面发挥重要作用，许多神经元投射通路都含有mGluRs。mGluRs有8种亚型，进一步分为I、II和III组。I组受体包括mGluR1和mGluR5，主要位于突触后部位。mGluR1在小脑、尾状核、壳核、丘脑、扣带回皮质和海马中呈中度至高密度分布，在脑桥中密度较低。mGluR5通常在额叶皮质、尾状核、壳核、伏隔核、嗅结节和海马中呈中度至高密度分布，在小脑中密度较低。mGluR1和mGluR5在调节神经元兴奋性方面与磷脂酶C呈正偶联（3）。mGluR1和mGluR5功能障碍与CNS中的多种疾病有关，包括焦虑症、抑郁症、精神分裂症、帕金森病以及药物成瘾或戒断（2,4）。靶向mGluR5的正电子发射断层扫描（PET）放射性配体可以在正常生理和病理条件下可视化并分析mGluR5的表达（4-8）。然而，仅对少数mGluR1配体进行了研究。-（4-（6-（异丙基氨基）嘧啶-4-基）-1,3-噻唑-2-基）-4-甲氧基--甲基苯甲酰胺（ITMM）被证明是一种具有纳摩尔亲和力（=12.6 nM）的选择性mGluR1拮抗剂，对mGluR5的抑制作用很小。藤永等人（9）用碳-11标记ITMM，制备了-（4-（6-（异丙基氨基）嘧啶-4-基）-1,3-噻唑-2-基）-4-[碳-11]甲氧基--甲基苯甲酰胺（[碳-11]ITMM），用于大鼠脑内mGluR1分布的PET成像。丰田原等人（10）在小鼠和人脑中评估了[碳-11]ITMM。[碳-11]ITMM被证明是一种适用于绘制人脑中mGluR1图谱的PET放射性配体。
