PROJECT SUMMARY Exogenous metal chelates play an important role not only in the biomedical sciences but also in clinical medicine. Metal chelates may be used for a variety of purposes that span both the diagnosis and treatment of disease. One way in which the utility of metal chelates can be expanded is by tagging molecules of biological interest. The biomolecule might be a protein, a fragment thereof, or any other relevant molecule, that has been discovered to play a particular role in disease progression. The technology for conjugating metal chelates to biomolecules is now well developed. An example of the application of this technology would be to tag a relevant biomolecule with a metal chelate that can be detected using a common imaging modality. In preclinical studies this allows us to learn more about disease, its progression and treatment. Translation to the clinic may facilitate personal treatment regimens to be prescribed, rather than a one size fits all approach. The down side to this approach, and the factor likely to limit clinical translation, is the inherent toxicity of metals should they be liberated from the chelate in which they were administered. Exogenous metal chelates are routinely used in clinical medicine and, providing that the excreted rapidly, they are safe. However, when these chelates are retained in the body for prolonged periods, adverse effects can arise. To prevent release of the metal it is necessary to ensure that the chelate is excreted much more quickly than the metal is able to escape from the chelate. The longer the chelate remains in the body the more likely the metal ion is to be released. The large biomolecules if interest for tagging with metal chelates either do not excrete at all, or do so very slowly. And this increases the likelihood that toxicity problems will arise resulting from release of the metal from the chelate. The inability to rapidly excrete the metal chelate tag limited the extent to which this approach can be applied to nonhuman primate studies and ultimately translated into the clinic. We will develop an adaptation to existing technology for tagging biomolecules with metals that is aimed at overcoming these limitations. The specific aim of this project is to insert a linker between biomolecule and metal chelate that will jettison the metal chelate after it has served its purpose. The small metal chelate thus released can then be quickly and safely excreted. This new linker would afford a method by which the metal chelate can both tag a relevant biomolecule and still be excreted in a timely manner. We anticipate that this adaptation will expand the utility of metal chelate tags to a broader range of biomedical applications and increase the scope for clinical translation.