The Effect of Antipsychotics on the High-Affinity State of D2 and D3 Receptors A Positron Emission Tomography Study With [11C]-(+)-PHNO

Context: Most antipsychotics are thought to have an effect on D-2 and D-3 receptors. The development of carbon 11-labeled (+)-4-propyl-9-hydroxynaphthoxazine ([C-11]-(+)-PHNO), the first agonist radioligand with higher affinity for D-3 than D-2 receptors, allows one to differentiate the effects of antipsychotics on high-affinity vs low-affinity sites of the D-2 receptor and on D-3 vs D-2 receptor subtypes. Objectives: To examine the effects of antipsychotics (clozapine, risperidone, or olanzapine) on the high-vs high-+low-affinity sites of the D-2 and D-3 receptors by comparing the [C-11]-(+)-PHNO and [C-11]raclopride binding in the D-3 receptor-rich (globus pallidus and ventral striatum) and D-2 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 [C-11]-(+)-PHNO and [C-11]raclopride. The second was a double-blind, placebo-controlled experiment to compare the effect of pramipexole (a D-3 receptor-preferring agonist) vs placebo on the increased [C-11]-(+)-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 [C-11]-(+)-PHNO and [C-11]raclopride. Results: The antipsychotic-treated patients showed high occupancies with both [C-11]-(+)-PHNO and [C-11]raclopride in the dorsal striatum, with [C-11]raclopride occupancies about 20% higher. Most strikingly, patients did not show any occupancy with [C-11]-(+)-PHNO in the globus pallidus as compared with normal controls or with their own scans using [C-11]raclopride. This unblocked [C-11]-(+)-PHNO signal was displaced by a single dose of pramipexole. Conclusions: Antipsychotics block both the high-and low-affinity states of the D-2 receptors across the brain, but antipsychotic treatment does not block the [C-11](+)-PHNO signal in the D-3 receptor-rich regions, despite the ongoing D-2 receptor blockade. This [C-11]-(+)PHNO signal in regions such as the globus pallidus seems increased despite antipsychotic treatment and is displaceable by a D-3 receptor-preferring agonist. The radiotracer [C-11]-(+)-PHNO and the data open up new avenues for exploring the potential therapeutic significance of the D-3 receptor in schizophrenia.