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 its 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. The mGluR1 is found in moderate to high density in the cerebellum, caudate, putamen, thalamus, cingulate cortex, and hippocampus, with low density in the pons. The mGluR5 is usually found in moderate to high density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, and hippocampus, whereas the density in the cerebellum is low. The 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) and single-photon emission tomography of radioligands targeting mGluR1 can visualize and analyze mGluR1 expression in normal physiological and pathological conditions. Several radioligands have been studied for imaging of mGluR1 in the brain (5). 6-[1-(2-(Fluoro-3-pyridyl)-5-methyl-1-1,2,3-triazol-4-yl]quinoline (FPTQ) was shown to be a selective mGluR1 with nanomolar affinity (3.6 nM), with little inhibition to mGluR5 (6). Fujinaga et al. (7) prepared and evaluated 6-[1-(2-[F] fluoro-3-pyridyl)-5-methyl-1-1,2,3-triazol-4-yl]quinoline ([F]FPTQ) for use with PET imaging of mGluR1 distribution in rats. The investigators concluded that [F]FPTQ is not suitable for PET imaging of GluR1 in the brain because of its rapid dissociation and the presence of radiolabeled metabolite in the 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GTP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。mGluR有八种亚型,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以中到高密度存在,在脑桥中密度较低。mGluR5通常在额叶皮质、尾状核、壳核、伏隔核、嗅结节和海马中以中到高密度存在,而在小脑中密度较低。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、抑郁、精神分裂症、帕金森病以及药物成瘾或戒断(2,4)。正电子发射断层扫描(PET)和针对mGluR1的放射性配体的单光子发射断层扫描可以在正常生理和病理条件下可视化和分析mGluR1的表达。已经研究了几种用于脑内mGluR1成像的放射性配体(5)。6-[1-(2-(氟-3-吡啶基)-5-甲基-1,2,3-三唑-4-基]喹啉(FPTQ)被证明是一种具有纳摩尔亲和力(3.6 nM)的选择性mGluR1,对mGluR5的抑制作用很小(6)。藤永等人(7)制备并评估了6-[1-(2-[F]氟-3-吡啶基)-5-甲基-1,2,3-三唑-4-基]喹啉([F]FPTQ)用于大鼠脑内mGluR1分布的PET成像。研究人员得出结论,[F]FPTQ由于其快速解离以及脑内存在放射性标记代谢物,不适合用于脑内GluR1的PET成像。