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. A number of recent studies have suggested that D2 and D3 receptors are regulated in an opposing manner in a variety of CNS disorders. For example, it has been reported that there is a 45% reduction in D3 receptors in the ventral striatum and a 15% increase in D2 receptors the caudate/putamen of postmortem brain samples of Parkinson's Disease. Other studies have shown an increase in D3 receptors and a decrease in D2 receptors in brain samples obtained following chronic exposure to cocaine. Therefore, the development of radiotracers having a high affinity for D3 versus D2 receptors, and vice versa, would be of tremendous interest to the imaging (PET and SPECT) and neuroscience (autoradiography) research community since it would enable the independent measurement of D2 and D3 receptors in a variety of CNS disorders. Our group was previously funded (through RFA MH-02-003) to develop PET and SPECT radiotracers having a high affinity and selectivity for D3 versus D2 receptors. The function of the current R21/R33 research project is to develop PET and SPECT radiotracers, selective for the D2 receptor which would compliment our ongoing research in the development of D3 receptor 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 D2 receptor in vivo. A secondary goal of this project is to develop an iodine-125 labeled radiotracer for in vitro binding studies of the D2 receptor. [unreadable] [unreadable] [unreadable]