TY - JOUR
T1 - The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia
AU - Gründer, Gerhard
AU - Landvogt, Christian
AU - Vernaleken, Ingo
AU - Buchholz, Hans Georg
AU - Ondracek, Jasmin
AU - Siessmeier, Thomas
AU - Härtter, Sebastian
AU - Schreckenberger, Mathias
AU - Stoeter, Peter
AU - Hiemke, Christoph
AU - Rösch, Frank
AU - Wong, Dean F.
AU - Bartenstein, Peter
N1 - Funding Information:
We thank Sabine Höhnemann and Markus Piel for performing the syntheses of [18F]fallypride, and Heike Armbrust for assistance in performing the PET studies. We gratefully acknowledge Martina Klein’s and Carsten Eulitz’ statistical advice. Parts of this work are included in Jasmin Ondracek’s doctoral thesis at the Medical Faculty of the University of Mainz. This study was supported by the University of Mainz (MAIFOR program), the Research Fund of the University of Mainz, the State Rheinland-Pfalz, and the German Research Council (DFG, grant Ba 1101/2-1).
PY - 2006/5
Y1 - 2006/5
N2 - Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p < 0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.
AB - Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D2/D3 dopamine receptors in human striatum. Here, the occupancy of D2/D3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [18F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D2/D3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, p < 0.005). While the maximum attainable receptor occupancy Emax approached 100% both in the striatum and cortex, the plasma concentration at 50% of Emax (ED50) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D2/D3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.
KW - Clozapine
KW - D receptor occupancy
KW - Positron emission tomography
KW - Schizophrenia
KW - [F]fallypride
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U2 - 10.1038/sj.npp.1300931
DO - 10.1038/sj.npp.1300931
M3 - Article
C2 - 16237387
AN - SCOPUS:33646137570
SN - 0893-133X
VL - 31
SP - 1027
EP - 1035
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 5
ER -