First human evidence of d-amphetamine induced displacement of a D-2/3 agonist radioligand: A [C-11]-(+)-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. [C-11]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D-2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [C-11]-(+)-PHNO is expected to bind preferentially to D2 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. [C-11]-(+)- 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 [C-11]-(+)- 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. [C-11]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D-2/3 antagonist radioligands.