Jucaite Aurelija, Cselényi Zsolt, Lappalainen Jaakko, McCarthy Dennis J, Lee Chi-Ming, Nyberg Svante, Varnäs Katarina, Stenkrona Per, Halldin Christer, Cross Alan, Farde Lars
Department of Clinical Neuroscience, AstraZeneca PET Center, Karolinska Institutet, R5:02, SE-17176, Stockholm, Sweden.
Department of Clinical Neuroscience, PET Centre, Karolinska Institutet, Stockholm, Sweden.
Psychopharmacology (Berl). 2017 Feb;234(4):707-716. doi: 10.1007/s00213-016-4506-4. Epub 2016 Dec 24.
Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA receptor positive modulators with limited sedative effects.
The current study aimed to confirm target engagement at GABA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABA receptor occupancy, and tolerability.
Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [C]flumazenil, were performed in 12 subjects at baseline and after administration of single oral doses of AZD7325 (0.2 to 30 mg) and AZD6280 (5 to 40 mg). PET images were analyzed using a simplified reference tissue model, and regional binding potentials (BP) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABA receptor occupancy was described by hyperbolic function, and K (plasma concentration required for 50% receptor occupancy) was estimated. Assessments of safety and tolerability included recording of adverse events, vital signs, electrocardiogram, and laboratory tests.
The [C]flumazenil binding was reduced in a dose-dependent, saturable manner by both agents. Maximum receptor occupancy could be reached for both compounds without causing sedation or cognitive impairment. The K estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively.
High GABA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.
镇静、依赖性和滥用可能性限制了非选择性γ-氨基丁酸（GABA）受体正向调节剂在焦虑症治疗中的应用。AZD7325和AZD6280是新型的、亚型选择性GABA受体正向调节剂，具有有限的镇静作用。
本研究旨在确认AZD7325和AZD6280在人体中对GABA受体的靶向作用，并确定暴露量、GABA受体占有率与耐受性之间的关系。
两项正电子发射断层扫描（PET）研究，使用高分辨率研究断层扫描（HRRT）和放射性配体[C]氟马西尼，在12名受试者的基线期以及单次口服AZD7325（0.2至30毫克）和AZD6280（5至40毫克）后进行。使用简化参考组织模型分析PET图像，并获得区域结合电位（BP）。用双曲线函数描述AZD7325或AZD6280的血浆浓度与GABA受体占有率之间的关系，并估算K （50%受体占有率所需的血浆浓度）。安全性和耐受性评估包括记录不良事件、生命体征、心电图和实验室检查。
两种药物均以剂量依赖性、可饱和的方式降低了[C]氟马西尼的结合。两种化合物均可达到最大受体占有率，且不会引起镇静或认知障碍。AZD7325和AZD6280的K 估算值分别为15和440纳摩尔/升。
AZD7325和AZD6280可在无明显镇静作用的情况下达到较高的GABA受体占有率。
