title: Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist.
abstract: BACKGROUND
  Dopamine D(3) receptors are involved in the pathophysiology of several neuropsychiatric conditions. [(11)C]-(+)-PHNO is a radiolabeled D(2) and D(3) agonist, suitable for imaging the agonist binding sites (denoted D(2HIGH) and D(3)) of these receptors with positron emission tomography (PET). PET studies in nonhuman primates documented that, in vivo, [(11)C]-(+)-PHNO displays a relative selectivity for D(3) compared with D(2HIGH) receptor sites and that the [(11)C]-(+)-PHNO signal is enriched in D(3) contribution compared with conventional ligands such as [(11)C] raclopride.
  
  
  METHODS
  To define the D(3) contribution (f(PHNO)(D3)) to [(11)C]-(+)-PHNO binding potential (BP(ND)) in healthy humans, 52 PET scans were obtained in 19 healthy volunteers at baseline and following oral administration of various doses of the selective D(3) receptor antagonist, GSK598809.
  
  
  RESULTS
  The impact of GSK598809 on [(11)C]-(+)-PHNO was regionally selective. In dorsal regions of the striatum, GSK598809 did not significantly affect [(11)C]-(+)-PHNO BP(ND) (f(PHNO)(D3) approximately 0%). Conversely, in the substantia nigra, GSK598809 dose-dependently reduced [(11)C]-(+)-PHNO binding to nonspecific level (f(PHNO)(D3) approximately 100%). In ventral striatum (VST), globus pallidus and thalamus (THA), [(11)C]-(+)-PHNO BP(ND) was attributable to a combination of D(2HIGH) and D(3) receptor sites, with f(PHNO)(D3) of 26%, 67% and 46%, respectively. D(3) receptor binding potential (BP(ND)(D3)) was highest in globus pallidus (1.90) and substantial nigra (1.39), with lower levels in VST (.77) and THA (.18) and negligible levels in dorsal striatum.
  
  
  CONCLUSIONS
  This study elucidated the pharmacologic nature of the [(11)C]-(+)-PHNO signal in healthy subjects and provided the first quantification of D(3) receptor availability with PET in the living human brain.
authors.affiliation: Clinical Imaging Centre, GlaxoSmithKline, London, United Kingdom. graham.e.searle@gsk.com
authors.forename: Graham
authors.initials: G
authors.lastname: Searle
authors.forename: John D
authors.initials: JD
authors.lastname: Beaver
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.forename: Massimo
authors.initials: M
authors.lastname: Bani
authors.forename: Andri
authors.initials: A
authors.lastname: Tziortzi
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Manolo
authors.initials: M
authors.lastname: Mugnaini
authors.forename: Cristiana
authors.initials: C
authors.lastname: Griffante
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo-Pich
authors.forename: Sylvain
authors.initials: S
authors.lastname: Houle
authors.forename: Roger
authors.initials: R
authors.lastname: Gunn
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000328:Adult; D053961:Azabicyclo Compounds / Q000008:administration & dosage; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010069:Oxadiazoles / Q000008:administration & dosage; D010078:Oxazines / Q000493:pharmacokinetics*; D010080:Oxazoles / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D053961:Azabicyclo Compounds; D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C000594007:GSK598809; C528328:GSK690693; D010069:Oxadiazoles; D010078:Oxazines; D010080:Oxazoles; D050637:Receptors, Dopamine D3; C042631:naxagolide