Exploring the use of a hydroxypyridinone decorporation agent for the removal of toxic residual gadolinium from MRI contrast agent administration

项目摘要/摘要 基于Gd的造影剂已广泛应用于临床磁共振 影像研究。然而，尽管它们有着出众的安全声誉，但严重的毒性问题 与这些药物的使用有关的研究在过去几年里出现了 展示了Gd的释放和随后在骨组织中的沉积 肾功能正常、血脑屏障完整的患者的大脑。唯一实用的 减少Gd沉积对健康影响的治疗方法是用螯合疗法 形成可排泄的络合物的试剂，尽管格拉像其他重金属一样是其中之一 最难处理的元素。在过去的三十年里，劳伦斯夫妇 伯克利国家实验室致力于口腔发育的研究项目 治疗鳗系元素去孔洞，导致活性药物的出现 配料3，4，3-Li(1，2-HOPO)作为一种特殊的吖系元素固定候选者。最初 由于民众对应对核威胁的暴露后医学对策的需求， 3，4，3-Li(1，2-HOPO)的开发遵循了一个参考动物规则的计划 由美国食品和药物管理局建立的审批路径，重点是 临床药理学和毒理学，处方优化，以及受控疗效 清除注入的有威胁的放射性同位素(钚、汞、钚、铀或 Ne)。此外，3，4，3-Li(1，2-HOPO)的口服配方使其成为第一个口服和 无可争议的最有效的治疗染料去孔化产品。《调查》 该药品于2014年8月获得新药(IND，112,264)状态。然而， 虽然临床前开发计划专注于展示杰出的 3，4，3-Li(1，2-HOPO)体内对放射性元素的脱孔效果 溶液热力学研究证实，它对其他f元素具有极高的亲和力， 包括Gd.在拟议的研究项目中，我们将探索潜在的3，4，3-Li(1，2-HOPO) 作为Gd脱孔剂，可在给药前、给药期间或给药后使用 以Gd为基础的造影剂。将使用已建立的模型进行动物研究，以 充分表征3，4，3-Li(1，2-HOPO)清除沉积Gd的效果 或者用于防止沉积，而不改变造影剂用于成像的效力。这个 通过该计划收集的数据将从已有的数据体中受益并被添加到数据体中 可用于IND批准的产品，这可能会导致扩大适应症和 对近期临床研究和应用的展望。

Project Summary/Abstract Gadolinium-based contrast agents have been widely used in clinical magnetic resonance imaging studies. However, despite their exceptional safety reputation, serious toxicity issues associated with the use of these agents have emerged in the last several years, with studies demonstrating the release of gadolinium (Gd) and subsequent deposition in bone tissue and in the brain in patients with normal renal function and intact blood-brain barriers. The only practical therapy to reduce the health consequences of gadolinium deposition is treatment with chelating agents that form excretable complexes, although gadolinium, like other heavy metals, is among the most intractable elements to decorporate. Over the past three decades, the Lawrence Berkeley National Laboratory has dedicated a research program to the development of oral therapeutics for actinide decorporation, leading to the emergence of the active pharmaceutical ingredient 3,4,3-LI(1,2-HOPO) as an exceptional candidate for actinide sequestration. Initially driven by the civilian need for post-exposure medical countermeasures against nuclear threats, the development of 3,4,3-LI(1,2-HOPO) followed a program that references the Animal Rule approval path established by the U.S. Food and Drug Administration, and focused on pre- clinical pharmacology and toxicology, formulation optimization, as well as controlled efficacy for the removal of injected threat radioisotopes (plutonium, americium, curium, uranium or neptunium). In addition, the oral formulation of 3,4,3-LI(1,2-HOPO) makes it the first oral and indisputably most efficacious therapeutic actinide decorporation product. The Investigational New Drug (IND, 112,264) status was obtained in August 2014 for this drug product. However, while the preclinical development program has focused on demonstrating the outstanding decorporation efficacy of 3,4,3-LI(1,2-HOPO) in vivo for radioactive actinides exclusively, recent solution thermodynamic studies have confirmed its extremely high affinity for other f-elements, including Gd. In the proposed research project, we will explore the potential 3,4,3-LI(1,2-HOPO) as a Gd decorporation agent that may be used in anticipation of, during, or after administration of Gd-based contrast agents. Animal studies using established models will be performed to adequately characterize the efficacy profile of 3,4,3-LI(1,2-HOPO) for eliminating deposited Gd or for preventing deposition, without altering the potency of the contrast agent for imaging. The data gathered through this program will benefit from and be added to the body of data already available for the IND-approved product, which may then lead to an enlarged indication and prospects of clinical studies and use in the very near future.