Over the past fifteen years there has been a tremendous amount of research conducted in the development of PET and SPECT radiotracers for studying dopamine D2 receptor function in vivo. This research has been largely driven by the availability of a number of antipsychotics possessing a high affinity for dopamine D2 receptors, and the alteration of D2 receptor density identified in postmortem brain samples from a variety of CNS disorders including schizophrenia, Parkinson's disease, Alzheimer's Disease, and substance abuse. However, the radiotracers that have been developed to date are not capable of discriminating between the different subtypes of the D2-class of receptors. For example, [11C]raclopride and [123I]IBZM bind with high affinity to dopamine D2 and D3 receptors, and [11C/18F]N-methylspiperone binds potently to D2, D3 and D4 receptors. Therefore, measurement of """"""""D2 receptor binding potential"""""""" obtained with these radiotracers consists of a composite of D2, D3, and, in the case of N-methylspiperone, D4 receptor density. Within the D2-class of receptors, a great deal of experimental evidence suggests that the D3 receptor plays a critical role in a number of CNS disorders. Furthermore, a number of recent studies suggest that there are differences in the regulation of D2 and D3 receptors in schizophrenia, Parkinson's disease, and cocaine abuse. Therefore, the development of radiotracers having a high affinity for D3 versus D2 receptors, and vice versa, would be of tremendous interest to the PET and SPECT research community. Over the past six years, our group has synthesized a number of heterocyclic and benzamide analogues having a high affinity and modest selectivity for D2 versus D3 receptors. The function of this R21/R33 research project is to develop PET and SPECT radiotracers, selective for the D3 receptor, based on these lead compounds. The goal of the R21 component of this project is to synthesize and characterize in vitro putative PET and SPECT radiotracers. Once potential radiotracers are identified, a series of detailed in vitro and in vivo studies will be conducted in the R33 Phase of the project as part of the ligand validation process. The goal of this research project is to develop one PET and one SPECT radiotracer that can be used in functional imaging studies of the D3 receptor in vivo. A secondary goal of this project is to develop an iodine-125 labeled radiotracer for in vitro binding studies of the D3 receptor.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA016181-02
Application #
6667092
Study Section
Special Emphasis Panel (ZRG1-SRB (06))
Program Officer
Grant, Steven J
Project Start
2002-09-30
Project End
2007-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$265,179
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Tu, Zhude; Li, Shihong; Li, Aixiao et al. (2013) Synthesis and in vitro pharmacological evaluation of indolyl carboxylic amide analogues as D3 dopamine receptor selective ligands. Medchemcomm 4:1283-1289
Mach, Robert H; Tu, Zhude; Xu, Jinbin et al. (2011) Endogenous dopamine (DA) competes with the binding of a radiolabeled D? receptor partial agonist in vivo: a positron emission tomography study. Synapse 65:724-32
Tu, Zhude; Li, Shihong; Xu, Jinbin et al. (2011) Effect of cyclosporin A on the uptake of D3-selective PET radiotracers in rat brain. Nucl Med Biol 38:725-39
Tu, Zhude; Li, Shihong; Cui, Jinquan et al. (2011) Synthesis and pharmacological evaluation of fluorine-containing D? dopamine receptor ligands. J Med Chem 54:1555-64
Wang, Qi; Mach, Robert H; Luedtke, Robert R et al. (2010) Subtype selectivity of dopamine receptor ligands: insights from structure and ligand-based methods. J Chem Inf Model 50:1970-85
Tu, Zhude; Xu, Jinbin; Jones, Lynne A et al. (2010) Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation. Nucl Med Biol 37:509-16
Xu, Jinbin; Hassanzadeh, Babak; Chu, Wenhua et al. (2010) [3H]4-(dimethylamino)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl) butyl)benzamide: a selective radioligand for dopamine D(3) receptors. II. Quantitative analysis of dopamine D(3) and D(2) receptor density ratio in the caudate-putamen. Synapse 64:449-59
Xu, Jinbin; Chu, Wenhua; Tu, Zhude et al. (2009) [(3)H]4-(Dimethylamino)-N-[4-(4-(2-methoxyphenyl)piperazin- 1-yl)butyl]benzamide, a selective radioligand for dopamine D(3) receptors. I. In vitro characterization. Synapse 63:717-28
Vangveravong, Suwanna; McElveen, Elizabeth; Taylor, Michelle et al. (2006) Synthesis and characterization of selective dopamine D2 receptor antagonists. Bioorg Med Chem 14:815-25

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