Desferrithiocin Analogue Actinide Decorporation Agents

描述（由申请人提供）：拟议项目的具体目标是加速基于去铁硫菌素的螯合剂的全面开发，以消除放射性核素。过去系统的结构-活性研究已经允许设计和合成类似物和衍生物，其保留脱铁硫菌素（DFT）的特殊铁螯合活性，同时消除其不良作用。该研究计划的假设是，可以采用类似的方法来利用DFT平台设计将有效地使锕系元素脱钙的配体。根据过去的经验，啮齿动物和灵长类动物中铁螯合作用的广泛研究结果，以及对现有科学文献的广泛审查，选择了一种配体基组，其中包括一些已经显示出脱铀的螯合剂，以代表目前用于脱铀的最佳候选物（VI），Th（IV）[Pu（IV）的替代物]和Eu（III）[Am（III）的替代物] J.啮齿动物系统研究（包括剂量-反应、药理学、毒理学和组织病理学研究）将在配体基组中鉴定对于U（VI）的脱钙最有效和毒性最小的DFT螯合剂，Th（IV）和Eu（III）。还将研究一种创新的新方法，使用MRI来表征所选螯合剂对Eu（III）在啮齿动物中的分布和消除的作用。最终，最有希望的候选螯合剂将在灵长类动物模型中进行评估，以提供人类有效性的最佳证据。 因此，拟定的研究将确定主要DFT螯合剂，以进入进一步的产品开发，并为研究设计提供关键数据，以前瞻性评估动物中的有效性和人体中的安全性。

DESCRIPTION (provided by applicant): 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 analogues and 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 represent the best available candidates at present for the decorporation of U(Vl), Th(IV) [a surrogate for Pu(lV)] and Eu(lll) [a surrogate for Am(lll)J. Systematic investigations in rodents (including dose-response, pharmacologic, toxicologic and histopathologic studies) will identify the DFT chelators in the ligand basis set that are most effective and least toxic for decorporation of U(Vl), Th(IV) and Eu(lll). An innovative new approach using 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 development and provide critical data for the design of studies to prospectively assess efficacy in animals and safety in humans.