The myriad physiological functions of γ-amino butyric acid (GABA) are mediated by the GABA-benzodiazepine receptor complex comprising of the GABAA, GABAB, and GABAC groups. The various GABAA subunits with region-specific distributions in the brain subserve different functional and physiological roles. For example, the sedative and anticonvulsive effects of classical benzodiazepines are attributed to the α1 subunit, and the α2 and α3 subunits mediate the anxiolytic effect. To optimize pharmacotherapies with improved efficacy and devoid of undesirable side effects for the treatment of anxiety disorders, subtype-selective imaging radiotracers are required to assess target engagement at GABA sites and determine the dose-receptor occupancy relationships. The goal of this work was to characterize, in nonhuman primates, the in vivo binding profile of a novel positron emission tomography (PET) radiotracer, [11C]ADO, which has been indicated to have functional selectivity for the GABAA α2/α3 subunits. High specific activity [11C]ADO was administrated to 3 rhesus monkeys, and PET scans of 120-minute duration were performed on the Focus-220 scanner. In the blood, [11C]ADO metabolized at a fairly rapid rate, with ∼36% of the parent tracer remaining at 30 minutes postinjection. Uptake levels of [11C]ADO in the brain were high (peak standardized uptake value of ∼3.0) and consistent with GABAA distribution, with highest activity levels in cortical areas, intermediate levels in cerebellum and thalamus, and lowest uptake in striatal regions and amygdala. Tissue kinetics was fast, with peak uptake in all brain regions within 20 minutes of tracer injection. The one-tissue compartment model provided good fits to regional time-activity curves and reliable measurement of kinetic parameters. The absolute test-retest variability of regional distribution volumes ( VT) was low, ranging from 4.5% to 8.7%. Pretreatment with flumazenil (a subtype nonselective ligand, 0.2 mg/kg, intravenous [IV], n = 1), Ro15-4513 (an α5-selective ligand, 0.03 mg/kg, IV, n = 2), and zolpidem (an α1-selective ligand, 1.7 mg/kg, IV, n = 1) led to blockade of [11C]ADO binding by 96.5%, 52.5%, and 76.5%, respectively, indicating the in vivo binding specificity of the radiotracer. Using the nondisplaceable volume of distribution ( VND) determined from the blocking studies, specific binding signals, as measured by values of regional binding potential ( BPND), ranged from 0.6 to 4.4, which are comparable to those of [11C]flumazenil. In conclusion, [11C]ADO was demonstrated to be a specific radiotracer for the GABAA receptors with several favorable properties: high brain uptake, fast tissue kinetics, and high levels of specific binding in nonhuman primates. However, subtype selectivity in vivo is not obvious for the radiotracer, and thus, the search for subtype-selective GABAA radiotracers continues.

中文翻译：

---

为GABAA受体复合物寻找亚型选择性PET显像剂：在非人类灵长类动物中放射性示踪剂[11C] ADO的评估。

γ-氨基丁酸（GABA）的多种生理功能是由包含GABAA，GABAB和GABAC基团的GABA-苯并二氮杂receptor受体复合物介导的。大脑中具有特定区域分布的各种GABAA亚基具有不同的功能和生理作用。例如，经典的苯二氮卓类药物的镇静和抗惊厥作用归因于α1亚基，而α2和α3亚基介导抗焦虑作用。为了优化药物疗法以提高疗效并避免不良反应，从而治疗焦虑症，需要使用亚型选择性成像放射示踪剂评估GABA位点的靶标结合并确定剂量受体的占用关系。这项工作的目的是要以非人类灵长类动物为特征，新型正电子发射断层扫描（PET）放射性示踪剂[11C] ADO的体内结合曲线，已表明对GABAAα2/α3亚基具有功能选择性。将高比活[11C] ADO施用给3只恒河猴，并在Focus-220扫描仪上进行120分钟的PET扫描。在血液中，[11C] ADO以相当快的速度代谢，注射后30分钟约有36％的母体示踪剂残留。大脑中[11C] ADO的摄取水平较高（峰值标准摄取值为〜3.0），并且与GABAA分布一致，皮质区域的活动水平最高，小脑和丘脑处于中等水平，纹状体区域和杏仁核的摄取最低。组织动力学很快，在示踪剂注射后20分钟内所有大脑区域的吸收达到峰值。单组织隔室模型提供了与区域时间活动曲线的良好拟合以及动力学参数的可靠测量。区域分布量（VT）的绝对重测变异性很低，范围从4.5％到8.7％。用氟马西尼（亚型非选择性配体，0.2 mg / kg，静脉内[IV]，n = 1），Ro15-4513（α5-选择性配体，0.03 mg / kg，IV，n = 2）和唑吡坦（an α1-选择性配体1.7 mg / kg，IV，n = 1）分别导致[11C] ADO结合的96.5％，52.5％和76.5％的阻断，表明放射性示踪剂的体内结合特异性。使用通过阻断研究确定的不可替代的分布体积（VND），通过区域结合电位（BPND）值测量的特异性结合信号的范围为0.6至4.4，与[11C]氟马西尼相当。总之，[11C] ADO被证明是GABAA受体的特异性放射性示踪剂，具有几个有利的特性：高大脑摄取，快速的组织动力学和在非人类灵长类动物中的高水平特异性结合。但是，体内的亚型选择性对于放射性示踪剂并不明显，因此，继续寻找亚型选择性GABAA放射性示踪剂。