Human exposure to radionuclides, whether from nuclear power plant incidents or radiological or nuclear weaponry, is of growing concern. The currently approved treatment of radionuclide exposure, besides dealing with the symptoms of radiation sickness, entails decorporation therapy by complexation of the α-, β-, and γ-emitters with diethylenetriamine pentaacetic acid, an approach that is limited by the low solubility of the chelant in physiological media and very limited transport of the chelant through membranes. While derivatization of the complexing agent can improve lipophilicity and hence make the treatment of large numbers of patients with an orally available drug possible, effective therapy is still limited to a few isotopes and hampered by the uncertain metabolic stability of the radionuclide complexes. Orally available prodrugs are being developed that show promise of decorporation of a wide range of radionuclide ions. Metabolic activation to convert the prodrugs into chelants and metabolic derivatization that relies on well understood biochemical processes can greatly enhance the treatment outcome. This project investigates synthetic pathways to and the utility of amino acid-based chelants with eight binding sites. Heteroatoms like nitrogen and oxygen are known to interact with metal ions in solution, proper spatial orientation of these binding sites makes the formation of stable chelant-metal ion complexes possible. Simple building blocks like ethanolamine, propanolamine, acrylic and acetic acid derivatives and hydroxylated amino acids are used. The utility of the chelants is being evaluated at this stage in the program by determining stabilities of complexes of non-radioactive isotopes of vanadium, lanthanum, europium, and praseodymium. Isothermal titration calorimetry in physiological media is the method of choice.

Prodrug approach to radionuclide decorporation

251st National Meeting (2016)

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