Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist.
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.
Searle
Graham
G
Clinical Imaging Centre, GlaxoSmithKline, London, United Kingdom. graham.e.searle@gsk.com
Beaver
John D
JD
Comley
Robert A
RA
Bani
Massimo
M
Tziortzi
Andri
A
Slifstein
Mark
M
Mugnaini
Manolo
M
Griffante
Cristiana
C
Wilson
Alan A
AA
Merlo-Pich
Emilio
E
Houle
Sylvain
S
Gunn
Roger
R
Rabiner
Eugenii A
EA
Laruelle
Marc
M
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
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