title: Blockade of the brain histamine H3 receptor by JNJ-39220675: preclinical PET studies with [¹¹C]GSK189254 in anesthetized baboon.
abstract: BACKGROUND
  The preclinical characterization of a series of aryloxypyridine amides has identified JNJ-39220675 ((4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone) as a high-affinity histamine H(3) receptor antagonist and a candidate for further drug development particularly in the treatment of alcohol-related behaviors.
  
  
  OBJECTIVE
  This study measured brain histamine H(3) receptor blockade by JNJ-39220675 (1 mg/kg) in the female baboon.
  
  
  METHODS
  Positron emission tomography imaging and [(11)C]GSK189254, a reversible high-affinity radiotracer with specificity for the histamine H(3) receptor, was used to measure histamine H(3) receptor availability at baseline and after i.v. and oral administration of JNJ-39220675 (1 mg/kg) in the anesthetized baboon. Histamine H(3) receptor availability was estimated as the total distribution volume (V (T)) in brain regions. The sensitivity of [(11)C]GSK189254 binding to injected mass and carryover effects was determined.
  
  
  RESULTS
  JNJ-39220675 produces robust (ca. 90 %) blockade of [(11)C]GSK189254 binding after i.v. and oral administration. After oral administration of JNJ-39220675 (1 mg/kg), the fractional receptor occupancy was >0.9 at 90 min with a slight increase from 90 to 240 min. Similar to prior studies in humans, V (T) was highly sensitive to the mass of GSK189254 with ED(50) estimated to be 0.16 μg/kg.
  
  
  CONCLUSIONS
  The robust blockade of binding of [(11)C]GSK189254 by JNJ-39220675 demonstrates that this compound readily penetrates the blood-brain barrier and occupies the histamine H(3) receptor after oral administration at low plasma concentrations (∼1 ng/cc) supporting further drug development for alcohol addiction and other disorders. This study corroborates prior reports of the high sensitivity of [(11)C]GSK189254 to injected mass at doses >0.1 μg/kg.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. logan@bnl.gov
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: Steven
authors.initials: S
authors.lastname: Sands
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Jiang
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.forename: Payton
authors.initials: P
authors.lastname: King
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D054828:Histamine H3 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010215:Papio; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D012680:Sensitivity and Specificity; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: C559587:(4-cyclobutyl-(1,4)diazepan-1-yl)-(6-(4-fluorophenoxy)pyridin-3-yl)methanone; D001381:Azepines; D001552:Benzazepines; D054828:Histamine H3 Antagonists; D011725:Pyridines; 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