title: Brain region binding of the D2/3 agonist [11C]-(+)-PHNO and the D2/3 antagonist [11C]raclopride in healthy humans.
abstract: The D(2) receptors exist in either the high- or low-affinity state with respect to agonists, and while agonists bind preferentially to the high-affinity state, antagonists do not distinguish between the two states. [(11)C]-(+)-PHNO is a PET D(2) agonist radioligand and therefore provides a preferential measure of the D(2) (high) receptors. In contrast, [(11)C]raclopride is an antagonist radioligand and thus binds with equal affinity to the D(2) high- and low-affinity states. The aim was to compare the brain uptake, distribution and binding characteristics between [(11)C]-(+)-PHNO and [(11)C]raclopride in volunteers using a within-subject design. Both radioligands accumulated in brain areas rich in D(2)/D(3)-receptors. However, [(11)C]-(+)-PHNO showed preferential uptake in the ventral striatum and globus pallidus, while [(11)C]raclopride showed preferential uptake in the dorsal striatum. Mean binding potentials were higher in the putamen (4.3 vs. 2.8) and caudate (3.4 vs 2.1) for [(11)C]raclopride, equal in the ventral-striatum (3.4 vs. 3.3), and higher in the globus pallidus for [(11)C]-(+)-PHNO (1.8 vs. 3.3). Moreover [(11)C]-(+)-PHNO kinetics in the globus pallidus showed a slower washout than other regions. One explanation for the preferential binding of [(11)C]-(+)-PHNO in the globus pallidus and ventral-striatum could be the presence of a greater proportion of high- vs. low-affinity receptors in these areas. Alternatively, the observed distribution could also be explained by a preferential binding of D(3)-over-D(2) with [(11)C]-(+)-PHNO. This differential binding of agonist vs. antagonist radioligand, especially in the critically important region of the limbic striatum/pallidum, offers new avenues to investigate the role of the dopamine system in health and disease.
authors.affiliation: PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Ariel
authors.initials: A
authors.lastname: Graff-Guerrero
authors.forename: Matthaeus
authors.initials: M
authors.lastname: Willeit
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ginovart
authors.forename: David
authors.initials: D
authors.lastname: Mamo
authors.forename: Romina
authors.initials: R
authors.lastname: Mizrahi
authors.forename: Pablo
authors.initials: P
authors.lastname: Rusjan
authors.forename: Irina
authors.initials: I
authors.lastname: Vitcu
authors.forename: Philip
authors.initials: P
authors.lastname: Seeman
authors.forename: Alan A
authors.initials: AA
authors.lastname: Wilson
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000328:Adult; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001931:Brain Mapping / Q000379:methods; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000378:metabolism / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000378:metabolism / Q000493:pharmacokinetics; D065127:Dopamine D2 Receptor Antagonists; D005260:Female; D005917:Globus Pallidus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism; D010078:Oxazines / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D020891:Raclopride / Q000378:metabolism / Q000493:pharmacokinetics*; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000378:metabolism; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010078:Oxazines; D017448:Receptors, Dopamine D2; C042631:naxagolide; D020891:Raclopride; D004298:Dopamine