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 (CBR) and peripheral benzodiazepine receptors (PBR). PBR is also known as translocator protein (TSPO). The CBR is found exclusively in the central nervous system on the membranes of neurons and is coupled to the γ-aminobutyric acid receptor/chloride channel (3). In contrast, the PBR is a mitochondrial protein found in brain and peripheral tissues (adrenal gland, heart, lung, kidney, and testis) (4). The brain has lower levels of PBR than do the peripheral tissues. 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 (8). [C]PK11195 has been developed as a PET agent for non-invasive studies of microglia and macrophage activation in the brain, lung, and heart. However, accumulation of this tracer in the brain is limited. -(2,5-Dimethoxybenzyl)--(5-fluoro-2-phenoxyphenyl)acetamide (DAA1106) was found to be a selective agonist for studying PBRs in the central nervous system (9, 10). DAA1106 was reported to have a higher affinity for PBRs in mitochondrial fractions of rat and monkey brains than did PK11195 (9, 10). 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]DAA1106 have been developed as potential PET ligands with highly selective and specific binding to PBR (11, 12). -Benzyl--methyl-2-[7,8-dihydro-7-(2-[F]fluoroethyl)-8-oxo-2-phenyl-9-purin-9-yl]acetamide ([F]FEDAC), which has an acetamide structure, has been evaluated for imaging PBR in the brain (13).
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（CBR）和外周苯二氮䓬类受体（PBR）。PBR也被称为转位蛋白（TSPO）。CBR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，PBR是一种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）。脑内的PBR水平低于外周组织。神经胶质细胞和巨噬细胞都含有高水平的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，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伴随的神经元损伤中所发生的那样。已使用1-(2-氯苯基)-N-[甲基-1-(1-甲基丙基)-3-异喹啉羧酰胺（[C]PK11195）通过正电子发射断层扫描（PET）对PBR进行研究，[C]PK11195是一种具有特异性PBR拮抗活性的异喹啉羧酰胺（8）。[C]PK11195已被开发为一种PET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。然而，这种示踪剂在脑中的积聚是有限的。-(2,5-二甲氧基苄基)-N-(5-氟-2-苯氧基苯基)乙酰胺（DAA1106）被发现是用于研究中枢神经系统中PBR的选择性激动剂（9,10）。据报道，DAA1106对大鼠和猴脑线粒体部分的PBR的亲和力高于PK11195（9,10）。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-[F]氟乙基-5-甲氧基苄基)乙酰胺（[F]FEDAA1106）和[C]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（11,12）。-苄基-N-甲基-2-[7,8-二氢-7-(2-[F]氟乙基)-8-氧代-2-苯基-9-嘌呤-9-基]乙酰胺（[F]FEDAC），其具有乙酰胺结构，已被评估用于脑内PBR的成像（13）。
