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. [C-11]-(+)-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, [ C-11]-(+)-PHNO displays a relative selectivity for D-3 compared with D-2HIGH receptor sites and that the [C-11]-(+)-PHNO signal is enriched in D-3 contribution compared with conventional ligands such as [C-11] raclopride. Methods: To define the D-3 contribution (f(PHNO)(D3)) to [C-11]-(+)-PHNO binding potential (BPND) 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 [C-11]-(+)-PHNO was regionally selective. In dorsal regions of the striatum, GSK598809 did not significantly affect [C-11]-(+)-PHNO BPND (f(PHNO)(D3) approximate to 0%). Conversely, in the substantia nigra, GSK598809 dose-dependently reduced [C-11]-(+)-PHNO binding to nonspecific level (f(PHNO)(D3) approximate to 100%). In ventral striatum (VST), globus pallidus and thalamus (THA), [C-11]-(+)-PHNO BPND 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 (BPNDD3) 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 [C-11]-(+)-PHNO signal in healthy subjects and provided the first quantification of D-3 receptor availability with PET in the living human brain.