First human evidence of d-amphetamine induced displacement of a D 2/3 agonist radioligand: A [11C]-(+)-PHNO positron emission tomography study

Abstract

Imaging the competition between D2/3 radioligands and endogenous dopamine is so far the only way to measure dopamine release in the living human brain. The dopamine D2 receptor exists in a high (D2high) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D2high only. [11C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [11C]-(+)-PHNO is expected to bind preferentially to D2high, 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. [11C]-(+)-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 [11C]-(+)-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 D2/3 agonist radioligand in humans. [11C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D2/3 antagonist radioligands. © 2008 Nature Publishing Group All rights reserved.