Leung Kam
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Neuronal α4β2 nicotinic cholinergic receptors (nAChRs) are part of a heterogeneous family of ligand-gated ion channels expressed in the central nervous system, where their activation by acetylcholine and nicotine causes a rapid increase in cellular permeability to ions, such as Na and Ca (1-3). Nicotinic receptors exist as pentamers (homomeric or heteromeric) in various brain regions and ganglia. There are nine subtypes of ligand-binding α receptors (α2 to α10) and four subtypes of structural β receptors (β2 to β5). nAChRs have been found to be involved in cognitive processes such as learning memory and control of movement in normal subjects. nAChR dysfunction has been implicated in a number of human diseases such as schizophrenia, Huntington's disease, Alzheimer's disease, and Parkinson's disease. nAChRs also play a significant role in nicotine addiction and other health problems associated with tobacco smoking. 3-[2(S)-2-Azetidinylmethoxy]pyridine (A-85380) is a highly potent and selective α4β2 nAChR agonist with subnanomolar affinity (4, 5). 6-[F]Fluoro-A-85380 and 2-[F]fluoro-A-85380 have been studied in humans as positron emission tomography (6) agents for α4β2 nAChR imaging in the brain for studying neuropsychiatric disorders. A-85380 has also been labeled as 5-[I]iodo-A-85380, which was developed as a single-photon emission computed tomography agent for the non-invasive study of α4β2 nAChR in the brain. On the other hand, there are some implications that homomeric α7 nAChRs may play a role in the pathophysiology of neuropsychiatric disorders (7-9). α7 nAChRs are highly expressed in the cerebral cortex, hippocampus, and subcortical limbic regions, which are involved in learning, memory, and information processing (10-12). 4-Bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate (SSR180711) has been shown to be a potent and selective partial agonist for α7 nAChRs with nanomolar affinity (13). 4-[C]Methylphenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate ([C]CHIBA-1001) has been developed as a PET agent for the noninvasive study of α7 nAChR in the brain (14). In this chapter, another α7 nAChR agonist, 2-(5-[C]methyl-hexahydro-pyrrolo[3,4-]pyrrol-2-yl)-xanthene-9-one ([C]A-844606) (15), is being evaluated as a useful PET imaging agent.
神经元α4β2烟碱型胆碱能受体（nAChRs）是配体门控离子通道异源家族的一部分，在中枢神经系统中表达，乙酰胆碱和尼古丁对其激活会使细胞对离子（如Na和Ca）的通透性迅速增加（1-3）。烟碱型受体在各种脑区和神经节中以五聚体（同源或异源）形式存在。有九种配体结合α受体亚型（α2至α10）和四种结构β受体亚型（β2至β5）。已发现nAChRs参与正常受试者的认知过程，如学习记忆和运动控制。nAChR功能障碍与多种人类疾病有关，如精神分裂症、亨廷顿舞蹈症、阿尔茨海默病和帕金森病。nAChRs在尼古丁成瘾及其他与吸烟相关的健康问题中也起重要作用。3-[2(S)-2-氮杂环丁烷基甲氧基]吡啶（A-85380）是一种高效且选择性的α4β2 nAChR激动剂，具有亚纳摩尔亲和力（4, 5）。6-[F]氟-A-85380和2-[F]氟-A-85380已在人体中作为正电子发射断层扫描（6）剂用于脑内α4β2 nAChR成像，以研究神经精神疾病。A-85380也已标记为5-[I]碘-A-85380，它被开发为用于脑内α4β2 nAChR无创研究的单光子发射计算机断层扫描剂。另一方面，有一些迹象表明同源性α7 nAChRs可能在神经精神疾病的病理生理学中起作用（7-9）。α7 nAChRs在大脑皮层、海马体和皮层下边缘区域高度表达，这些区域参与学习、记忆和信息处理（10-12）。4-溴苯基-1,4-二氮杂双环(3.2.2)壬烷-4-羧酸盐（SSR180711）已被证明是一种具有纳摩尔亲和力的高效且选择性的α7 nAChR部分激动剂（13）。4-[C]甲基苯基-1,4-二氮杂双环(3.2.2)壬烷-4-羧酸盐（[C]CHIBA-1001）已被开发为用于脑内α7 nAChR无创研究的正电子发射断层扫描剂（14）。在本章中，另一种α7 nAChR激动剂2-(5-[C]甲基-六氢-吡咯并[3,4-]吡咯-2-基)-占吨-9-酮（[C]A-844606）（15）正在被评估为一种有用的正电子发射断层扫描成像剂。
