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.
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