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A Positron Emission Tomography Study With [¹¹C]-(+)-PHNO

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

Arch Gen Psychiatry. 2009;66(6):606-615.

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.

Author Affiliations: Positron Emission Tomography Centre, Centre for Addiction and Mental Health (Drs Graff-Guerrero, Mamo, Shammi, Mizrahi, Rusjan, Houle, Wilson, and Kapur and Mss Marcon and Barsoum) and Department of Psychiatry, University of Toronto (Drs Graff-Guerrero, Mamo, Shammi, Mizrahi, Houle, Wilson, and Kapur), Toronto, Ontario, Canada; Institute of Neurobiology, Universidad Naciónal Autonoma de México, Mexico City (Dr Graff-Guerrero); and Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, London, England (Dr Kapur).

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