1. ¹Positron Emission Tomography Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
2. ²Department of General Psychiatry, Medical University Vienna, Vienna, Austria
3. ³Département de Psychiatrie, Unité de Neuroimagerie, Université de Genève, Genève, Switzerland
4. ⁴Department of Psychiatry, University of Toronto, Toronto, ON, Canada
5. ⁵Institute of Neurobiology, UNAM, Mexico City, Mexico
6. ⁶Department of Pharmacology, University of Toronto, Toronto, ON, Canada

Correspondence: Dr S Kapur, PET Centre, Centre for Addiction and Mental Health, University of Toronto, 250 College Street, Toronto, ON, Canada M5T 1R8, Tel: 416 535 8501 x6176, Fax: 416 260 4164, E-mail: Shitij_Kapur@camh.net

Received 20 October 2006; Revised 15 February 2007; Accepted 15 February 2007; Published online 4 April 2007.

Abstract

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 D₂ receptor exists in a high (D₂^high) and a low-affinity state for dopamine. Under physiological conditions, dopamine is expected to bind to D₂^high only. [¹¹C]-(+)-4-propyl-9-hydroxynaphthoxazine ((+)-PHNO) is the first D_2/3 agonist radioligand for positron emission tomography (PET) imaging in humans. Since [¹¹C]-(+)-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. [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 D_2/3 agonist radioligand in humans. [¹¹C]-(+)-PHNO PET might be a superior measure for release of endogenous dopamine than PET employing conventional D_2/3 antagonist radioligands.