Imaging Dopamine D3 Receptors in the Human Brain with Positron Emission Tomography, [11C]PHNO, and a Selective D3 Receptor Antagonist

BackgroundDopamine D3 receptors are involved in the pathophysiology of several neuropsychiatric conditions. [11C]-(+)-PHNO is a radiolabeled D2 and D3 agonist, suitable for imaging the agonist binding sites (denoted D2HIGH and D3) of these receptors with positron emission tomography (PET). PET studies in nonhuman primates documented that, in vivo, [11C]-(+)-PHNO displays a relative selectivity for D3 compared with D2HIGH receptor sites and that the [11C]-(+)-PHNO signal is enriched in D3 contribution compared with conventional ligands such as [11C] raclopride.MethodsTo define the D3 contribution (fPHNOD3) to [11C]-(+)-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 D3 receptor antagonist, GSK598809.ResultsThe impact of GSK598809 on [11C]-(+)-PHNO was regionally selective. In dorsal regions of the striatum, GSK598809 did not significantly affect [11C]-(+)-PHNO BPND (fPHNOD3 ≈ 0%). Conversely, in the substantia nigra, GSK598809 dose-dependently reduced [11C]-(+)-PHNO binding to nonspecific level (fPHNOD3 ≈ 100%). In ventral striatum (VST), globus pallidus and thalamus (THA), [11C]-(+)-PHNO BPND was attributable to a combination of D2HIGH and D3 receptor sites, with fPHNOD3 of 26%, 67% and 46%, respectively. D3 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.ConclusionsThis study elucidated the pharmacologic nature of the [11C]-(+)-PHNO signal in healthy subjects and provided the first quantification of D3 receptor availability with PET in the living human brain.