First Human Evidence of d -Amphetamine Induced Displacement of a D 2/3 Agonist Radioligand: A [ 11 C]-(+)-PHNO Positron Emission Tomography Study

Imaging the competition between D 2/3 radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D 2 receptor exists in a high (D 2 high ) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D 2 high only. [ 11 C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D 2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [ 11 C]-(+)-PHNO is expected to bind preferentially to D 2 high , it should be particularly vulnerable to competition with endogenous dopamine. Nine healthy subjects participated in two PET scans, one after administration of d -amphetamine and one after placebo. [ 11 C]-(+)-PHNO PET test re-test variability was determined in 11 healthy subjects. Binding potentials (BPs) were calculated for caudate, putamen, ventral striatum, and globus pallidus. d -Amphetamine led to a significant decrease of [ 11 C]-(+)-PHNO BPs in caudate (−13.2%), putamen (−20.8%), and ventral striatum (−24.9%), but not in globus pallidus (−6.5%). d -Amphetamine-induced displacement correlated with serum d -amphetamine levels in all regions but caudate. This is the first report on competition between endogenous dopamine and a D 2/3 agonist radioligand in humans. [ 11 C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D 2/3 antagonist radioligands.