Abstract
Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [18F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.
Footnotes
This work was supported by an Investigator Initiated Study Award from Ortho-McNeil Janssen Scientific Affairs, LLC; a Merit Award from the Office of Research and Development, Department of Veterans Affairs (to E.C.M.); the National Institutes of Health National Institute on Drug Abuse [Grant K02 DA0000517] (to L.L.H.); and the National Institutes of Health National Center for Research Resources [Grant P51-RR000165] (to Yerkes National Primate Research Center).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- D2R
- D2 family dopamine receptor
- ANOVA
- analysis of variance
- BP
- binding potential
- CSF
- cerebrospinal fluid
- DVR
- distribution volume ratio
- MRI
- magnetic resonance imaging
- PAL
- paliperidone
- PET
- positron emission tomography
- PFC
- prefrontal cortex
- dlPFC
- dorsolateral PFC
- oPFC
- orbital PFC
- mPFC
- medial PFC
- RIS
- risperidone
- ROI
- region of interest
- TCtx
- temporal cortex.
- Received October 19, 2011.
- Accepted December 28, 2011.
- U.S. Government work not protected by U.S. copyright
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