GABAA receptor occupancy by subtype selective GABAAα2,3 modulators: PET studies in humans

Aurelija Jucaite, Zsolt Cselényi, Jaakko Lappalainen, Dennis J McCarthy, Chi-Ming Lee, Svante Nyberg, Katarina Varnäs, Per Stenkrona, Christer Halldin, Alan Cross, Lars Farde, Aurelija Jucaite, Zsolt Cselényi, Jaakko Lappalainen, Dennis J McCarthy, Chi-Ming Lee, Svante Nyberg, Katarina Varnäs, Per Stenkrona, Christer Halldin, Alan Cross, Lars Farde

Abstract

Rationale: Sedation, dependence, and abuse liability limit the use of non-selective γ-aminobutyric acid (GABAA) receptor positive modulators for the treatment of anxiety. AZD7325 and AZD6280 are novel, subtype-selective GABAAα2,3 receptor positive modulators with limited sedative effects.

Objectives: The current study aimed to confirm target engagement at GABAA receptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAA receptor occupancy, and tolerability.

Method: Two PET studies, using high-resolution research tomography (HRRT) and the radioligand [11C]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 (BPND) were obtained. The relationship between plasma concentration of AZD7325 or AZD6280 and GABAA 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 [11C]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 GABAA receptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.

Trial registration: ClinicalTrials.gov NCT00681720 NCT00681746.

Keywords: AZD6280; AZD7325; Agonist; Anxiety; GABAA receptors; PET; [11C]flumazenil.

Conflict of interest statement

Compliance with ethical standardsConflict of interestsThe studies were funded by AstraZeneca, R&D, Södertälje, Sweden [ClinicalTrials.gov identifier D1140C00007, NCT00681720 and D0850C00011, NCT00681746]. AstraZeneca was involved in original concepts and systematic review of existing trial evidence, the design, the control of the allocation schedule, the conduct of the trial, the collection and monitoring of data, data analysis, and interpretation, and the writing and approval of this report. The authors have had full control of all primary data and agree to allow the journal to review the data if requested.DisclosuresAuthors AJ, ZC, JL, DJMc, SN, CML, AC, and LF were full-time AstraZeneca employees during the study design, conduct, data analysis, and writing period and received salary and stock from AstraZeneca. Authors KV, PS, and CH declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Flowchart of the two PET studies with GABAA agonists AZD7325 and AZD6280
Fig. 2
Fig. 2
a Parametric PET images of [11C]flumazenil binding to brain GABAA receptors at baseline and after oral administration of 2 and 30 mg of AZD7325 (PET images obtained using wavelet-aided parametric mapping (Cselényi et al. 2002) and fused with MR images; BPND binding potential; individual subject). b Time curves for radioactivity in the occipital cortex following administration of AZD7325 in the human subject. c Relationship between receptor occupancy and plasma exposure. Result of a model fit to the data (Eq. 2). The figure demonstrates regional maximum occupancy differences in relation to the differences in the fraction of GABAA receptor subunits in the region (CER cerebellum, OC occipital cortex, PUT putamen, AMG amygdala). Ki,plasma, best fit estimate, and 95% CI, obtained on the logarithmic scale, was 15 nmol/ml; 95% CI 10–24 nmol/l
Fig. 3
Fig. 3
a Parametric PET images of [11C]flumazenil binding to brain GABAA receptors at baseline and after oral administration of 5 and 30 mg of AZD6280 (PET images fused with MR images; BPND binding potential; individual subject). b Time curves for radioactivity in the occipital cortex after intravenous injection of [11C]flumazenil at baseline and following administration of AZD6280 in the human subject. c Relationship between receptor occupancy and plasma exposure. Result of a model fit to the data (Eq. 2). The figure demonstrates regional maximum occupancy differences in relation to the differences in the fraction of receptor subunits in the region (CER cerebellum, OC occipital cortex, PUT putamen, AMG amygdala). Ki,plasma, best fit estimate, and 95% CI, obtained on the logarithmic scale, was 440 nmol/ml; 95% CI 197–982 nmol/ml

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