Abstract
Measuring the in vivo occupancy of antipsychotic drugs at dopamine D2 and D3 receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [11C]-(+)-PHNO is D3-preferring, allowing estimates of the relative D2 and D3 binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [11C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D2 and D3 receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of [11C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBPND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D2 and D3 fractions of [11C]-(+)-PHNO BPND in six brain regions, was used to infer occupancy at D2 and D3 receptors. BPND following antipsychotic challenge decreased in all regions. Estimated D2 : D3 selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D3 receptors in vivo, and that the lack of D3 occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.
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Acknowledgements
This study was funded by the Lieber Center for Schizophrenia Research and partly by GlaxoSmithKline. The authors gratefully acknowledge the expert technical contributions of Elizabeth Hackett, John Castrillon and Sung A Bae.
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RRG has received research support from Janssen and Lilly through APIRE and a travel stipend from Lilly, Forest, and Elsevier Science through the Society of Biological Psychiatry. RNG and EAR are employees of GlaxoSmithKline. In the last 3 years, AA has received honoraria from BMS-Otsuka, Boehringer-Ingelheim, Lundbeck, and Sanofi-Aventis, as well as research support from GlaxoSmithKline. In the last 3 years, MS has served as a consultant for Amgen, and GlaxoSmithKline, and has received research support from Intracellular Therapies, XX, NM, and BE have no conflicts of interest to disclose.
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Girgis, R., Xu, X., Miyake, N. et al. In Vivo Binding of Antipsychotics to D3 and D2 Receptors: A PET Study in Baboons with [11C]-(+)-PHNO. Neuropsychopharmacol 36, 887–895 (2011). https://doi.org/10.1038/npp.2010.228
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DOI: https://doi.org/10.1038/npp.2010.228
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