The antipsychotic effects of typical neuroleptics are mediated by blockade of dopamine D2 type receptors. It has been proposed that the antipsychotic effects of these drugs are mediated by blockade of cortical and limbic dopamine D2 receptors while extrapyramidal site effects are mediated by dorsolateral striatal D2 receptor blockade. To date, most PET and SPECT studies of antipsychotic drug blockade of D2 receptors have examined the striatum. There are a number of studies which suggest that the atypical profile of clozapine is mediated at least in part by selective effects on cortical and limbic dopaminergic neurotransmission. Our group has developed [18F] N-allyl-5-fluoropropylepidepride as a PET radioligand for visualization of extrastriatal D2 receptors in man. Our Phase I and early Phase II IND studies demonstrate that this ligand allows excellent visualization and quantitation of extrastriatal D2 receptors in man. Wed propose to use [18F] N-allyl-5-fluoropropylepidepride PET studies to evaluate 15 schizophrenic subjects off medication and following 6 weeks of haloperidol monotherapy, as well as 15 schizophrenic subjects off medication and following 8 weeks of clozapine monotherapy. The data from these studies will allow evaluation as to whether clozapine, s compared to haloperidol (a typical neuroleptic), selectively occupies extrastriatal dopamine D2 receptors, and whether regional occupancy of D2 receptors can be related to antipsychotic effects. Secondary goals include examining if psychopathological symptom complexes, i.e., positive, negative, and disorganization, as well as cognitive abnormalities in schizophrenia are related to regional levels of D2 receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060898-03
Application #
6490869
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (03))
Program Officer
Brady, Linda S
Project Start
2000-01-01
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2002
Total Cost
$350,560
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Zald, David H; Woodward, Neil D; Cowan, Ronald L et al. (2010) The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: a principal component analysis of [18F]fallypride binding. Neuroimage 51:53-62
Woodward, Neil D; Zald, David H; Ding, Zhaohua et al. (2009) Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study. Neuroimage 46:31-8
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Riccardi, Patrizia; Li, Rui; Ansari, Mohammad Sib et al. (2006) Amphetamine-induced displacement of [18F] fallypride in striatum and extrastriatal regions in humans. Neuropsychopharmacology 31:1016-26
Riccardi, Patrizia; Zald, David; Li, Rui et al. (2006) Sex differences in amphetamine-induced displacement of [(18)F]fallypride in striatal and extrastriatal regions: a PET study. Am J Psychiatry 163:1639-41
Kessler, Robert M; Ansari, M Sib; Riccardi, Patrizia et al. (2006) Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 31:1991-2001