This application describes a collaborative program to develop non-invasive tools for the study of the molecular and biochemical mechanisms of central dopaminergic neurotransmission. The primary neurochemical abnormality in many dopamine (DA) function-associated diseases appears to be the alterations of dopamine levels in the brain, which may be caused by dysfunctional systems located presynaptic and/or postsynaptic to the dopaminergic system itself. Measurement of such abnormalities may be possible via positron emission tomography (PET) and single photon emission computed tomography (SPECT). During Phase I, we propose to prepare nonradioactive ligands and evaluate their binding affinity and selectivity as dopamine agonists or as inhibitors of the DA uptake site. Convenient radiolabeling precursors will be prepared and radiolabeled with either 18F, 99mTc or 11C. The proposed program will identify promising ligands for PET and SPECT imaging studies which may be used to evaluate the development and progression of various psychiatrist disorders and also to gauge treatment effectiveness for these disorders. The choice of radionuclides (11C, 18F, 99mTc) is designed to permit the use of the proposed ligands in clinical and research settings of varied function and sophistication.
