谷氨酸受体的分子成像综述

A Review of Molecular Imaging of Glutamate Receptors.

作者信息

Kim Jong-Hoon, Marton János, Ametamey Simon Mensah, Cumming Paul

机构信息

Neuroscience Research Institute, Gachon University, Incheon 21565, Korea.

Gachon Advanced Institute for Health Science and Technology, Graduate School, Incheon 21565, Korea.

出版信息

Molecules. 2020 Oct 16;25(20):4749. doi: 10.3390/molecules25204749.

Abstract

Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (-methyl--aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

摘要

正电子发射断层扫描(PET)和单光子发射计算机断层扫描(SPECT)分子成像技术是一种成熟且重要的体内技术,用于评估基本生物学过程并揭示神经递质受体在各种神经精神疾病中的作用。有特定的配体可用于多巴胺、5-羟色胺和阿片受体的PET/SPECT研究,但用于哺乳动物脑中主要兴奋性神经递质谷氨酸受体的放射性示踪剂的相应开发却滞后了。尽管谷氨酸神经传递在脑生理学以及中风、癫痫、精神分裂症和神经退行性疾病等病症中具有核心重要性,但这种情况仍持续存在。近年来,人们为开发用于离子型(N-甲基-D-天冬氨酸(NMDA)、海人藻酸和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/使君子氨酸受体)和代谢型谷氨酸受体(I、II和III型代谢型谷氨酸受体)亚型分子成像的有用配体付出了巨大努力。我们现在综述谷氨酸受体成像放射性配体的发展状况,主要强调现有配体在可靠的体内应用中的适用性。我们简要介绍了选定分子的放射合成方法。一般来说,除了NMDA受体GluN2B亚基的配体外,开发用于离子型谷氨酸受体成像的放射性示踪剂几乎没有成功;体内PCP/MK801结合位点配体未能成功的原因无疑与其对离子通道开放、未阻断状态的依赖性有关。许多在体外具有良好结合特性的AMPA和海人藻酸受体配体在活体脑中未能产生可测量的特异性结合。这可能反映了开发用于氨基酸受体的脑渗透性配体的挑战,再加上体内构象差异。代谢型谷氨酸受体成像的情况较好,特别是对于代谢型谷氨酸受体5亚型。几种成功的PET配体可用于在精神分裂症、抑郁症、药物滥用和衰老等病症中研究代谢型谷氨酸受体。考虑到谷氨酸能信号在脑功能中的核心地位和多样性,我们用于离子型和代谢型谷氨酸受体分子成像的选择性和灵敏工具相对较少。针对谷氨酸受体特定亚型和亚基的进一步放射性药物研究可能会开拓新的研究视野,并在基础和临床研究中得到广泛应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/31d2/7587586/4a5d8cc03b4c/molecules-25-04749-g001.jpg

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