title: In vivo quantification of regional dopamine-D3 receptor binding potential of (+)-PHNO: Studies in non-human primates and transgenic mice.
abstract: Examination of dopamine-D3 (D3) receptors with positron emission tomography (PET) have been hampered in the past by the lack of a PET ligand with sufficient selectivity for D3 over dopamine-D2 (D2) receptors. The two types co-localize in the brain, with D2 density significantly higher than D3, hence nonselective PET ligands inform on D2, rather than D3 status. [(11)C]-(+)-PHNO is a novel PET ligand with a preferential affinity for D3 over D2. We used the selective D3 antagonist, SB-277011 to dissect regional fractions of the [(11)C]-(+)-PHNO signal attributable to D3 and D2 in primate brain. The results were compared with quantitative autoradiography with (3)H-(+)-PHNO in wild-type, D2-knock-out, and D3-knock-out mice examined at baseline and following administration of SB-277011. Both sets of results converged to indicate a predominant D3-related component to (+)-PHNO binding in extra-striatal regions, with binding in the midbrain being entirely attributable to D3. The midbrain is thus an excellent target region to examine D3 receptor occupancy with [(11)C]-(+)-PHNO PET in vivo.
authors.affiliation: GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, London, UK. eugenii_a_rabiner@gsk.com
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Jose
authors.initials: J
authors.lastname: Nobrega
authors.forename: Christophe
authors.initials: C
authors.lastname: Plisson
authors.forename: Mickael
authors.initials: M
authors.lastname: Huiban
authors.forename: Roger
authors.initials: R
authors.lastname: Raymond
authors.forename: Mustansir
authors.initials: M
authors.lastname: Diwan
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Patrick
authors.initials: P
authors.lastname: McCormick
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gentile
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Marc A
authors.initials: MA
authors.lastname: Laruelle
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000378:metabolism; D008636:Mesencephalon / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism*; D048530:Papio anubis; D049268:Positron-Emission Tomography; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D009570:Nitriles; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; C042631:naxagolide; D004298:Dopamine