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小鼠大脑中的γ-氨基丁酸(GABA)受体亚型:通过体内[F]氟马西尼正电子发射断层扫描(PET)进行区域定位和地西泮受体占有率分析

GABA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [F]flumazenil PET.

作者信息

Müller Herde Adrienne, Benke Dietmar, Ralvenius William T, Mu Linjing, Schibli Roger, Zeilhofer Hanns Ulrich, Krämer Stefanie D

机构信息

Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

出版信息

Neuroimage. 2017 Apr 15;150:279-291. doi: 10.1016/j.neuroimage.2017.02.022. Epub 2017 Feb 10.

Abstract

Classical benzodiazepines, which are widely used as sedatives, anxiolytics and anticonvulsants, exert their therapeutic effects through interactions with heteropentameric GABA receptors composed of two α, two β and one γ2 subunit. Their high affinity binding site is located at the interface between the γ2 and the adjacent α subunit. The α-subunit gene family consists of six members and receptors can be homomeric or mixed with respect to the α-subunits. Previous work has suggested that benzodiazepine binding site ligands with selectivity for individual GABA receptor subtypes, as defined by the benzodiazepine-binding α subunit, may have fewer side effects and may even be effective in diseases, such as schizophrenia, autism or chronic pain, that do not respond well to classical benzodiazepines. The distributions of the individual α subunits across the CNS have been extensively characterized. However, as GABA receptors may contain two different α subunits, the distribution of the subunits does not necessarily reflect the distribution of receptor subtypes with respect to benzodiazepine pharmacology. In the present study, we have used in vivo [F]flumazenil PET and in vitro [H]flumazenil autoradiography in combination with GABA receptor point-mutated mice to characterize the distribution of the two most prevalent GABA receptor subtypes (α1 and α2) throughout the mouse brain. The results were in agreement with published in vitro data. High levels of α2-containing receptors were found in brain regions of the neuronal network of anxiety. The α1/α2 subunit combinations were predictable from the individual subunit levels. In additional experiments, we explored in vivo [F]flumazenil PET to determine the degree of receptor occupancy at GABA receptor subtypes following oral administration of diazepam. The dose to occupy 50% of sensitive receptors, independent of the receptor subtype(s), was 1-2mg/kg, in agreement with published data from ex vivo studies with wild type mice. In conclusion, we have resolved the quantitative distribution of α1- and α2-containing homomeric and mixed GABA receptors in vivo at the millimeter scale and demonstrate that the regional drug receptor occupancy in vivo at these GABA receptor subtypes can be determined by [F]flumazenil PET. Such information should be valuable for drug development programs aiming for subtype-selective benzodiazepine site ligands for new therapeutic indications.

摘要

经典苯二氮䓬类药物被广泛用作镇静剂、抗焦虑药和抗惊厥药,它们通过与由两个α、两个β和一个γ2亚基组成的异源五聚体GABA受体相互作用发挥治疗作用。它们的高亲和力结合位点位于γ2与相邻α亚基之间的界面处。α亚基基因家族由六个成员组成,受体在α亚基方面可以是同聚体或混合体。先前的研究表明,对由苯二氮䓬结合α亚基定义的个体GABA受体亚型具有选择性的苯二氮䓬结合位点配体可能副作用较少,甚至可能对精神分裂症、自闭症或慢性疼痛等对经典苯二氮䓬类药物反应不佳的疾病有效。各个α亚基在中枢神经系统中的分布已得到广泛表征。然而,由于GABA受体可能包含两种不同的α亚基,这些亚基的分布不一定反映出与苯二氮䓬药理学相关的受体亚型的分布。在本研究中,我们结合使用体内[F]氟马西尼PET和体外[H]氟马西尼放射自显影技术以及GABA受体点突变小鼠,来表征两种最普遍的GABA受体亚型(α1和α2)在整个小鼠脑中的分布。结果与已发表的体外数据一致。在焦虑相关神经元网络的脑区发现了高水平的含α2受体。α1/α2亚基组合可根据各个亚基水平预测。在额外的实验中,我们探索了体内[F]氟马西尼PET,以确定口服地西泮后GABA受体亚型的受体占有率。占据50%敏感受体的剂量,与受体亚型无关,为1 - 2mg/kg,这与野生型小鼠离体研究的已发表数据一致。总之,我们在体内以毫米尺度解析了含α1和α2的同聚体和混合GABA受体的定量分布,并证明可以通过[F]氟马西尼PET确定体内这些GABA受体亚型的区域药物受体占有率。这些信息对于旨在开发用于新治疗适应症的亚型选择性苯二氮䓬位点配体的药物研发项目应该是有价值的。

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