Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Curr Top Med Chem. 2011;11(7):860-86. doi: 10.2174/156802611795165142.
The (18 kDa) Translocator Protein (TSPO), was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named "Peripheral-type benzodiazepine receptor (PBR)". It is an evolutionarily well-conserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity.
（18 kDa）转位蛋白（TSPO）最初于 1977 年被鉴定为苯二氮䓬类药物地西泮的外周结合位点，并被命名为“外周型苯二氮䓬受体（PBR）”。它是一种进化上高度保守的蛋白质，特别位于外/内膜线粒体接触位点，与 32 kDa 电压依赖性阴离子通道（VDAC）和 30 kDa 腺嘌呤核苷酸转运体（ANT）密切相关，从而形成线粒体通透性转换孔（MPTP）。TSPO 在周围组织（类固醇产生组织、肝脏、心脏、肾脏、肺、免疫系统）中广泛表达，在中枢神经系统中表达水平较低，主要位于神经胶质细胞和神经元中。TSPO 参与多种生物学过程，如胆固醇转运、类固醇生成、钙稳态、脂质代谢、线粒体氧化、细胞生长和分化、细胞凋亡诱导以及免疫功能调节。在过去的十年中，许多研究报告称，TSPO 的基础表达在许多人类疾病中发生改变，如癌症和神经退行性疾病（亨廷顿病和阿尔茨海默病），以及各种形式的脑损伤、炎症和焦虑。因此，TSPO 不仅被认为是许多治疗应用（抗惊厥、抗焦虑、免疫调节等）的有前途的药物靶点，而且还作为相关疾病状态和进展的有效诊断标志物，促使开发特定的标记配体作为成像技术的有力工具。已经报道了许多结构不同的配体类，它们对 TSPO 表现出高亲和力和选择性。事实上，这些配体中的大多数都是从选择性 CBR 配体设计而来，这些配体的结构经过修饰以提高其对 TSPO 的亲和力。进行了广泛的构效关系研究，提出了各种 TSPO 药效团模型。本文的目的是强调获得具有高亲和力和选择性的 TSPO 配体所需的结构要求。
