GABA(A) receptor occupancy by subtype selective GABA(Aα2,3) modulators: PET studies in humans

RATIONALE: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABA(A)) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABA(Aα2,3) receptor positive modulators with limited sedative effects. OBJECTIVES: The current study aimed to confirm target engagement at GABA(A) receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABA(A) receptor occupancy, and tolerability. METHOD: Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [(11)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(ND)) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABA(A) receptor occupancy was described by hyperbolic function, and K (i,plasma) (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. RESULTS: The [(11)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 (i,plasma) estimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively. CONCLUSION: High GABA(A) receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00213-016-4506-4) contains supplementary material, which is available to authorized users.