title: Unexpectedly high affinity of a novel histamine H(3) receptor antagonist, GSK239512, in vivo in human brain, determined using PET.
abstract: OBJECTIVE
  This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H(3) receptors (RO) in healthy human volunteers.
  
  
  METHODS
  PET scans were obtained after i.v. administration of the H(3) -specific radioligand [(11) C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan.
  
  
  RESULTS
  Following administration of GSK239512, there was a reduction in the brain uptake of [(11) C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL(-1) . This corresponds to a free concentration of 4.50 × 10(-12 ) M (pK = 11.3).
  
  
  CONCLUSIONS
  The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose.
authors.affiliation: GlaxoSmithKline Clinical Imaging Centre, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ashworth
authors.forename: A
authors.initials: A
authors.lastname: Berges
authors.forename: E A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: A A
authors.initials: AA
authors.lastname: Wilson
authors.forename: R A
authors.initials: RA
authors.lastname: Comley
authors.forename: R Y K
authors.initials: RY
authors.lastname: Lai
authors.forename: R
authors.initials: R
authors.lastname: Boardley
authors.forename: G
authors.initials: G
authors.lastname: Searle
authors.forename: R N
authors.initials: RN
authors.lastname: Gunn
authors.forename: M
authors.initials: M
authors.lastname: Laruelle
authors.forename: V J
authors.initials: VJ
authors.lastname: Cunningham
mesh_terms: D000328:Adult; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D006633:Histamine Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: D001552:Benzazepines; D006633:Histamine Antagonists; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide
keywords: H3 receptors; PET study; drug development; pharmacokinetics; receptor occupancy