title: Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369.
abstract: BACKGROUND
  The serotonin 5-HT(1B) receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT(1B) receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT(1B) receptor antagonist with potential antidepressant properties.
  
  
  OBJECTIVE
  To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT(1B) receptors using PET and the radioligand [(11)C]AZ10419369.
  
  
  METHODS
  PET studies with [(11)C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1-40 mg).
  
  
  RESULTS
  After administration in non-human primates and human subjects, AZD3783 reduced regional [(11)C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K (i,plasma)) for monkeys was 25 and 27 nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18 nmol/L, respectively.
  
  
  CONCLUSIONS
  The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT(1B) receptors with a similar in vivo affinity for human and monkey receptors. [(11)C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT(1B) receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT(1B) receptor compounds.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Karolinska University Hospital, Stockholm, Sweden. Katarina.Varnas@ki.se
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.forename: Svante
authors.initials: S
authors.lastname: Nyberg
authors.forename: Per
authors.initials: P
authors.lastname: Karlsson
authors.forename: M Edward
authors.initials: ME
authors.lastname: Pierson
authors.forename: Matts
authors.initials: M
authors.lastname: Kågedal
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Cselényi
authors.forename: Dennis
authors.initials: D
authors.lastname: McCarthy
authors.forename: Alan
authors.initials: A
authors.lastname: Xiao
authors.forename: Minli
authors.initials: M
authors.lastname: Zhang
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000378:metabolism*; D010879:Piperazines; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals; D044302:Receptor, Serotonin, 5-HT1B / Q000187:drug effects* / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000378:metabolism*; D013045:Species Specificity; D055815:Young Adult
chemical_list: C558331:(2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide; C530629:5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-morpholin-4-yl-phenyl)amide; D001578:Benzopyrans; D009025:Morpholines; D010879:Piperazines; D019275:Radiopharmaceuticals; D044302:Receptor, Serotonin, 5-HT1B; D058829:Serotonin 5-HT1 Receptor Antagonists