title: GABAAreceptor occupancy by subtype selective GABAAα2,3modulators: PET studies in humans.
abstract: 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 GABAAα2,3receptor positive modulators with limited sedative effects.
  
  
  
  The current study aimed to confirm target engagement at GABAAreceptors by AZD7325 and AZD6280 in humans and to determine the relationship between exposure, GABAAreceptor occupancy, and tolerability.
  
  
  
  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 GABAAreceptor occupancy was described by hyperbolic function, and Ki,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.
  
  
  
  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 Ki,plasmaestimates for AZD7325 and AZD6280 were 15 and 440 nmol/l, respectively.
  
  
  
  High GABAAreceptor occupancy by AZD7325 and AZD6280 could be reached without clear sedative effects.
authors.affiliation: Department of Clinical Neuroscience, AstraZeneca PET Center, Karolinska Institutet, R5:02, SE-17176, Stockholm, Sweden. Aurelija.Jucaite@astrazeneca.com.|Department of Clinical Neuroscience, PET Centre, Karolinska Institutet, Stockholm, Sweden. Aurelija.Jucaite@astrazeneca.com.
authors.forename: Aurelija
authors.initials: A
authors.lastname: Jucaite
authors.affiliation: 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.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Cselényi
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.|Marinus Pharmaceuticals, Radnor, PA, USA.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Lappalainen
authors.affiliation: AstraZeneca R&D, Södertälje, Sweden.|Independent Consultant, Newark, DE, USA.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: McCarthy
authors.affiliation: AstraZeneca R&D, Södertälje, Sweden.|Ever East Consultants Limited, Hong Kong, People's Republic of China.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Lee
authors.affiliation: AstraZeneca R&D, Södertälje, Sweden.|Department of Psychiatry, Karolinska University Hospital (Huddinge), Stockholm, Sweden.
authors.forename: Svante
authors.initials: S
authors.lastname: Nyberg
authors.affiliation: Department of Clinical Neuroscience, PET Centre, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Department of Clinical Neuroscience, PET Centre, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Stenkrona
authors.affiliation: Department of Clinical Neuroscience, PET Centre, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Cross
authors.affiliation: 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.
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D005442:Flumazenil; D018757:GABA Modulators / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology*; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D011963:Receptors, GABA-A / Q000378:metabolism*; D055815:Young Adult
chemical_list: C576237:4-amino-8-(2-fluoro-6-methoxy-phenyl)-N-propylcinnoline-3-carboxamide; D018757:GABA Modulators; D006574:Heterocyclic Compounds, 2-Ring; D011963:Receptors, GABA-A; D005442:Flumazenil
keywords: AZD6280; AZD7325; Agonist; Anxiety; GABAA receptors; PET; [11C]flumazenil