The intent of this Proposal is the preparation, evaluation and validation of new radiopharmaceuticals for neurological PET studies, based on the monoamine (dopamine, norepinephrine, and serotonin) reuptake systems. A large number of clinical problems in degenerative neuronal diseases, major psychiatric illnesses, and drug abuse involve the monoamine neurotransmitter systems. The non-invasive, in vivo study of these systems can be best approached using Positron Emission Tomography, but such studies will require the availability of specific, well characterized radiotracers. It is the goal of this project to provide such radiopharmaceuticals. Target molecules for the dopamine, norepinephrine and serotonin reuptake systems have been chosen, and synthetic routes to their radiolabeling with either carbon-11 or fluorine-18 devised. Each new radiochemical will be tested in a wide variety of preclinical tests for pharmacologic specificity and kinetic properties. The goal is the development of radiotracers which are specific for a single binding site, and whose kinetic properties allow precise identification of the parameter of interest (binding to the reuptake site) and its distinction from non-specific processes involved in ligand distribution (blood flow, vascular permeability and non-specific binding). The regional and pharmacological specificity of new radiotracers will be examined in small animals using ex vivo, in vitro, and autoradiographic methodologies. Physiochemical parameters (log P, protein binding) will be determined in vitro. Formation and biodistribution of radiolabeled metabolites in blood and brain will be examined. As the final pre-clinical step, PET studies of radiotracer distribution in primate brain will be completed and the development and evaluation of mathematical models undertaken. Promising radiopharmaceuticals at this point will undergo determination of radiation dosimetry and toxicology and preliminary-human studies completed to allow evaluation of the kinetic model using human data. Overall, this represents a cohesive, structured approach to the development of new radiopharmaceuticals for PET. New quantitative PET techniques for the study of the monoamine systems will permit direct evaluation of disease-related hypotheses in neurology, psychiatry, and drug abuse research.
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