Desferrithiocin Analogue Actinide Decorporation Agents

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The specific goal of the proposed project is to accelerate the overall development of desferrithiocin- based chelating agents for decorporation of radionuclides. Past systematic structure-activity studies have allowed the design and synthesis of analoguesand derivatives which retain the exceptional iron-chelating activity of desferrithiocin (DFT) while eliminating its adverse effects. The hypothesis underlying the research program is that a similar approach can be adopted to utilize the DFT platform for the design of ligands that will effectively decorporate actinides. On the basis of past experience, the results of extensive studies of iron chelation in rodents and primates, and a wide-ranging review of the available scientific literature, a ligand basis set which includes a number of chelators already shown to decorporate uranium was selected to rep- resent the best available candidates at presentfor the decorporationof U(VI), Th(IV) [a surrogate for Pu(IV)] and Eu(lll) [a surrogate for Am(lll)]. Systematic investigations in rodents (including dose-response, pharma- cologic, toxicologic and histopathologic studies) will identify the DFT chela'tors in the ligand basis set that are most effective and least toxic for decorporationof U(VI), Th(IV) and Eu(lll). An innovative new approach us- ing MRI to characterize the action of a selected chelator on distribution and elimination of Eu(lll) in rodents will also be examined. Ultimately, the most promising candidate chelators will be evaluated in a primate model to provide the best available evidence for efficacy in humans. Accordingly, the proposed research will identify the lead DFT chelator(s) to enter further product devel- opment and provide critical data for the design of studies to prospectively assess efficacy in animals and safety in humans.