Leung Kam
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD,
Benzodiazepines are potent psychoactive drugs used for their sedative and anxiolytic properties (1, 2). There are two types of benzodiazepine receptors, which have been designated as central benzodiazepine receptors (CBRs) and peripheral benzodiazepine receptors (PBRs). CBRs are found exclusively in the central nervous system on the membranes of neurons and are coupled to the γ-aminobutyric acid receptor/chloride channel (3). In contrast, PBRs are mitochondrial proteins found in the brain and peripheral tissues (adrenal gland, heart, lung, kidney, and testis) (4); the brain has lower levels of PBR than do the peripheral tissues, and both glial cells and macrophages contain high levels of PBR (5-7). Increased PBR expression after brain injury or neuroinflammation is associated with microglial activation, such as occurs with the neuronal damage that accompanies several neurodegenerative diseases, including Alzheimer’s disease, Wernicke’s encephalopathy, multiple sclerosis, and epilepsy. PBRs have been studied with positron emission tomography (PET) using 1-(2-chlorophenyl)--[C]methyl--(1-methylpropyl)-3-isoquinoline carboxamide ([C]PK11195), an isoquinoline carboxamide with specific PBR antagonistic activity. [C]PK11195 has been developed as a PET agent for non-invasive studies of microglia and macrophage activation in the brain, lung, and heart [PuBMed]. However, accumulation of this tracer in the brain is limited. -(2,5-Dimethoxybenzyl)--(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106) is a selective agonist used to study PBRs in the central nervous system (8, 9). DAA1106 was reported to have a higher affinity for PBRs in mitochondrial fractions of rat and monkey brains than PK11195 (8, 9). Therefore, both tracers are able to cross the normal cell membrane to reach the mitochondrial receptor sites. -(5-Fluoro-2-phenoxyphenyl)--(2-[F]fluoroethyl-5-methoxybenzyl)acetamide ([F]FEDAA1106) and C-labeled DAA1106 ([C]DAA1106) have been developed as potential PET ligands with highly selective and specific binding to PBR. -Acetyl--(2-methoxybenzyl)-2-phenoxy-5-pyridinamine (PBR28), which has an aryloxyanilide structure, has been shown to have high affinity and selectivity for PBR (10). -Acetyl--(2-[C]methoxybenzyl)-2-phenoxy-5-pyridinamine ([C]PBR28) has been developed for imaging PBR in the brain (11). -Acetyl--(2-[F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([F]FEPPA), an analog of [C]PBR28, is being evaluated as a PET imaging agent for PBR in the brain (12).
苯二氮䓬类是具有镇静和抗焦虑特性的强效精神活性药物（1, 2）。苯二氮䓬类受体有两种类型，分别被命名为中枢苯二氮䓬类受体（CBRs）和外周苯二氮䓬类受体（PBRs）。CBRs仅存在于中枢神经系统中神经元的膜上，并与γ-氨基丁酸受体/氯离子通道偶联（3）。相比之下，PBRs是存在于脑和外周组织（肾上腺、心脏、肺、肾和睾丸）中的线粒体蛋白（4）；脑内PBR的水平低于外周组织，并且神经胶质细胞和巨噬细胞中都含有高水平的PBR（5 - 7）。脑损伤或神经炎症后PBR表达增加与小胶质细胞活化有关，例如在包括阿尔茨海默病、韦尼克脑病、多发性硬化症和癫痫在内的几种神经退行性疾病所伴随的神经元损伤中就会出现这种情况。已经使用1-(2-氯苯基)-N-[11C]甲基-N-(1-甲基丙基)-3-异喹啉羧酰胺([11C]PK11195)，一种具有特定PBR拮抗活性的异喹啉羧酰胺，通过正电子发射断层扫描（PET）对PBRs进行了研究。[11C]PK11195已被开发为一种PET试剂，用于对脑、肺和心脏中的小胶质细胞和巨噬细胞活化进行非侵入性研究[医学文献数据库]。然而，这种示踪剂在脑中的蓄积是有限的。-(2,5-二甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺（DAA1106）是一种用于研究中枢神经系统中PBRs的选择性激动剂（8, 9）。据报道，DAA1106对大鼠和猴脑线粒体组分中的PBRs的亲和力高于PK11195（8, 9）。因此，这两种示踪剂都能够穿过正常细胞膜到达线粒体受体位点。-(5-氟-2-苯氧基苯基)-N-(2-[18F]氟乙基-5-甲氧基苄基)乙酰胺([18F]FEDAA1106)和碳-11标记的DAA1106([11C]DAA1106)已被开发为对PBR具有高度选择性和特异性结合的潜在PET配体。-乙酰基-N-(2-甲氧基苄基)-2-苯氧基-5-吡啶胺（PBR28），其具有芳氧基苯胺结构，已被证明对PBR具有高亲和力和选择性（10）。-乙酰基-N-(2-[11C]甲氧基苄基)-2-苯氧基-5-吡啶胺([11C]PBR28)已被开发用于脑内PBR成像（11）。-乙酰基-N-(2-[18F]氟乙氧基苄基)-2-苯氧基-5-吡啶胺([18F]FEPPA)，[11C]PBR28的类似物，正在作为脑内PBR的PET成像剂进行评估（12）。
