The Effect of Antipsychotics on the High-Affinity State of D-2 and D-3 Receptors: A Positron Emission Tomography Study With [C-11]-(+)-PHNO

Ariel Graff-Guerrero, David Mamo, C. M. Shammi, Romina Mizrahi, Heidi Marcon, Penny Barsoum, Pablo Rusjan, Sylvain Houle, Alan A. Wilson, Shitij Kapur

Research output: Contribution to journalConference paper

93 Citations (Scopus)


Context Most antipsychotics are thought to have an effect on D2 and D3 receptors. The development of carbon 11–labeled (+)-4-propyl-9-hydroxynaphthoxazine ([11C]-(+)-PHNO), the first agonist radioligand with higher affinity for D3 than D2 receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D2 receptor and on D3 vs D2 receptor subtypes.

Objectives To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high- vs high- + low-affinity sites of the D2 and D3 receptors by comparing the [11C]-(+)-PHNO and [11C]raclopride binding in the D3 receptor–rich (globus pallidus and ventral striatum) and D2 receptor–rich (caudate and putamen) regions.

Design Two sequential studies with different participants and appropriate controls were performed. The first compared the occupancy produced by 3 antipsychotics as measured with [11C]-(+)-PHNO and [11C]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D3 receptor–preferring agonist) vs placebo on the increased [11C]-(+)-PHNO signal observed in the globus pallidus of patients.

Setting Positron Emission Tomography Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Participants Twenty-three patients with schizophrenia and 23 healthy controls.

Main Outcome Measures Antipsychotic occupancies as measured with [11C]-(+)-PHNO and [11C]raclopride.

Results The antipsychotic-treated patients showed high occupancies with both [11C]-(+)-PHNO and [11C]raclopride in the dorsal striatum, with [11C]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [11C]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [11C]raclopride. This unblocked [11C]-(+)-PHNO signal was displaced by a single dose of pramipexole.

Conclusions Antipsychotics block both the high- and low-affinity states of the D2 receptors across the brain, but antipsychotic treatment does not block the [11C]-(+)-PHNO signal in the D3 receptor–rich regions, despite the ongoing D2 receptor blockade. This [11C]-(+)-PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D3 receptor–preferring agonist. The radiotracer [11C]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D3 receptor in schizophrenia.
Original languageEnglish
Pages (from-to)606 - 615
Number of pages10
JournalJAMA Psychiatry
Issue number6
Publication statusPublished - Jun 2009
EventDopamine 50th Year Congress 2007 - Gothenburg, Sweden
Duration: 31 May 2007 → …


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