Desferrithiocin Analogue Actinide Decorporation Agents

去铁硫星类似物锕系装饰剂

• 批准号: 7586364
• 负责人: Raymond Joseph Bergeron
• 金额: $ 67.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586364
• 关键词: Actinoid Series Elements; Adopted; Adverse effects; Animals; Chelating Activity; Chelating Agents; Classification; Data; Development; Dose; Goals; Human; Investigation; Iron Chelating Agents; Iron Chelation; Lead; Ligands; Literature; Magnetic Resonance Imaging; Modeling; Numbers; Primates; Radioisotopes; Range; Research; Research Design; Rodent; Safety; Structure; Uranium; analog; base; desferrithiocin; design; experience; innovation; novel strategies; programs; response

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.

拟议项目的具体目标是加速去铁硫菌素的全面开发- 用于放射性核素脱附的螯合剂。以往系统的构效关系研究 允许设计和合成类似物和衍生物， 去铁硫菌素（DFT）的活性，同时消除其不良反应。这项研究的假设是 该程序的一个优点是，可以采用类似的方法来利用DFT平台设计配体， 能有效地分解锕系元素根据过去的经验，对铁的广泛研究的结果 螯合作用在啮齿动物和灵长类动物，并广泛审查现有的科学文献，配体 基组包括一些已经显示出能使铀脱附的螯合剂， 推荐目前用于测定U（VI）、Th（IV）[Pu（IV）的替代物]的最佳候选物 和Eu（III）[Am（III）的替代物]。啮齿类动物的系统研究（包括剂量-反应、药物- 生物学、毒理学和组织病理学研究）将在配体基组中鉴定DFT螯合剂， 对U（VI）、Th（IV）和Eu（III）的去除效果最好，毒性最小。一种创新的方法- 用MRI表征所选螯合剂对Eu（III）在啮齿动物体内分布和消除的作用 也将被审查。最终，最有希望的候选螯合剂将在灵长类动物中进行评估 模型，以提供人体有效性的最佳证据。 因此，拟议的研究将确定主要的DFT螯合剂，以进入进一步的产品开发。 为前瞻性评估动物疗效的研究设计提供关键数据， 人类的安全。