Chopra Arvind
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD 20894
The -methyl-d-aspartate (NMDA) receptor (NMDAR) belongs to a sub-group of the glutamate receptor family and has a heteromeric structure that is made up of three subunits (NR1, NR2, and NR3) as dimeric combinations (NR1/NR2 or NR1/NR3). There are four subtypes of NR2 (NR2A–NR2D), and NR3 has two subtypes, NR3A and NR3B. The NMDAR can bind several different types of ligands and has important functions in the process of learning and in the performance of memory tasks in a variety of animal species (invertebrate and vertebrate) (1, 2). These receptors are involved in the development of neurological conditions such as Parkinson’s disease, Alzheimer’s disease, bipolar disorder, etc (2, 3). The structure, distribution, and function of the NMDAR in the rodent brain has been reviewed elsewhere (1, 4). The NR1 subunit of the NMDAR is known to be distributed in all parts of the brain; of the different NR2 subtypes, NR2A is found throughout the brain, whereas NR2B, NR2C, and NR2D are present mainly in the forebrain (including the cerebral cortex, hippocampus, and the olfactory lobes), cerebellum, and the lower brain stem, respectively. High levels of the NR3A subtype are detected in many brain regions of only prenatal and newborn mice, whereas NR3B levels are low during these developmental stages. However, the NR3 subtype is expressed predominantly in the adult brain (4). Among the different NR2 and NR3 subunits, primarily the NR2B subunit is believed to modulate the various physiological and pharmacological activities of the NMDAR as mentioned above. Attempts to study the distribution of the NMDAR that contains the NR2B subunit in the brain through the use of positron emission tomography with radiolabeled compounds have been unsuccessful because the tracers lack binding specificity for the receptor (3). However, among these tracers, inspite of a high non-specific uptake of 6-{3-[4-(4-fluorobenzyl)piperidino]propionyl}-3-benzoxazol-2-[C]-one ([C]EMD-95885; a benzimidazole derivative) in the rodent brain the amount of radioactivity in the organ was reduced by pretreatment of the animals with ifenprodil, a selective antagonist of the NR2B subunit, suggesting that [C]EMD-95885 could be a suitable platform for the development of new imaging probes to study the location and distribution of the NMDAR that contains the NR2B subunit in the rodent brain (3). Results from assays demonstrated that novel compounds with a structure resembling EMD-95885 maintained their affinity for the NR2B subunit (5). On the basis of this information, Fuchigami et al. synthesized a series of [I]-labeled benzimidazole derivatives and investigated their receptor binding and brain uptake characteristics in normal mice (3). Among these radioiodinated compounds, only two, 2-{[4-(4-[I]iodobenzyl)piperidin-1-yl]methyl}benzimidazol-5-ol ([I]) and -{2-[4-(4-[I]iodobenzyl)-piperidin-1-ylmethyl]benzoimidazol-5-yl}-methanesulfonamide ([I]), were shown to have a high affinity for the NR2B subunit under conditions. This chapter discusses the and results obtained with [I]; the characteristics of [I] are described in a separate chapter of MICAD (www.micad.nih.gov) (6).
N-甲基-D-天冬氨酸（NMDA）受体（NMDAR）属于谷氨酸受体家族的一个亚组，具有异源结构，由三个亚基（NR1、NR2和NR3）以二聚体组合（NR1/NR2或NR1/NR3）构成。NR2有四种亚型（NR2A - NR2D），NR3有两种亚型，即NR3A和NR3B。NMDAR能结合几种不同类型的配体，在多种动物物种（无脊椎动物和脊椎动物）的学习过程及记忆任务执行中具有重要功能（1, 2）。这些受体参与帕金森病、阿尔茨海默病、双相情感障碍等神经疾病的发展过程（2, 3）。啮齿动物脑中NMDAR的结构、分布和功能在其他地方已有综述（1, 4）。已知NMDAR的NR1亚基分布于脑的所有部位；在不同的NR2亚型中，NR2A在全脑均有发现，而NR2B、NR2C和NR2D分别主要存在于前脑（包括大脑皮层、海马体和嗅叶）、小脑和脑桥下部。仅在产前和新生小鼠的许多脑区检测到高水平的NR3A亚型，而在这些发育阶段NR3B水平较低。然而，NR3亚型主要在成年脑中表达（4）。在不同的NR2和NR3亚基中，主要认为NR2B亚基调节上述NMDAR的各种生理和药理活性。通过使用放射性标记化合物的正电子发射断层扫描来研究含NR2B亚基的NMDAR在脑中的分布的尝试未成功，因为这些示踪剂对该受体缺乏结合特异性（3）。然而，在这些示踪剂中，尽管6-{3-[4-(4-氟苄基)哌啶基]丙酰基}-3-苯并恶唑-2-[C]-酮（[C]EMD - 95885；一种苯并咪唑衍生物）在啮齿动物脑中的非特异性摄取较高，但用NR2B亚基的选择性拮抗剂ifenprodil对动物进行预处理后，器官中的放射性量减少，这表明[C]EMD - 95885可能是开发新的成像探针以研究含NR2B亚基的NMDAR在啮齿动物脑中的位置和分布的合适平台（3）。实验结果表明，结构类似于EMD - 95885的新型化合物对NR2B亚基保持其亲和力（5）。基于此信息，Fuchigami等人合成了一系列[I]标记的苯并咪唑衍生物，并研究了它们在正常小鼠中的受体结合和脑摄取特性（3）。在这些放射性碘化化合物中，只有两种，2-{[4-(4-[I]碘苄基)哌啶-1-基]甲基}苯并咪唑-5-醇（[I]）和-{2-[4-(4-[I]碘苄基)-哌啶-1-基甲基]苯并咪唑-5-基}-甲磺酰胺（[I]），在特定条件下对NR2B亚基表现出高亲和力。本章讨论用[I]获得的实验和结果；[I]的特性在MICAD（www.micad.nih.gov）的单独一章中描述（6）。
