The goal of this project is the development of new and improved radiopharmaceuticals designed to allow nuclear medicine to exploit the attractive nuclear properties of a number of metallic radionuclides. The main focus of the project will be the development of blood flow tracers labeled with generator-produced positron-emitting nuclides (copper-62 and gallium-68). Such tracers might facilitate more widespread use of positron emission tomography (PET) in clinical diagnosis by reducing the dependence of PET centers on nuclides that require in-house cyclotron production. Some studies in technetium chemistry are also proposed, again emphasizing the potential role of these compounds as perfusion tracers. Underlying these efforts is a desire to elucidate principles of inorganic chemistry and drug design that might find broad general application in research to deliver new metal-labeled radiopharmaceuticals. Metal complexes, possessing properties believed to be important for achieving tissue uptake in proportion to regional rates of blood flow, will be prepared and characterized at both macroscopic (10-3 10-1M) and tracer concentrations. These radiolabeled metal complexes will be screened to evaluate their potential as radiopharmaceuticals by determination of their biodistribution in rats following intravenous injection. Such studies will serve to identify the best tracers for further evaluation. In addition, the biodistribution studies will provide data for the definition of structure-activity relationships describing the molecular features vital to tracer uptake and tracer retention in tissues of interest (brain, heart, kidney, and tumor). The most promising tracers identified in the studies with rats will be further assessed in animal models by comparison of their tissue uptake with blood flow measured using standard reference tracers (labeled microspheres and iodoantipyrine). PET imaging experiments with the copper-62 tracers already developed will be conducted in collaboration with Professors Steven R. Bergmann and Marcus E. Raichle at Washington University, allowing the performance of these compounds to be evaluated relative to standard cyclotron-produced PET tracers in animal model systems. Synthetic work with the copper (II) bis(thiosemicarbazone) complexes already developed will also continue, in order to refine their preparation into a convenient and reliable kit formulation for use with the eluent of a copper-62 generator.
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