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

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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.