Metal Catalyzed Dynamic Exchange Approach to 14-C Labeled Pharmaceuticals

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This CRD proposal will support the research collaboration between Prof. Arndtsen at McGill University and Dr. Gauthier at Merck. The research is directed towards creating a more efficient method to generate carbon-14 radiolabeled pharmaceuticals. Radiolabeled drugs, and in particular those incorporating carbon-14, are required for all molecules in the clinical development. These labeled materials are used to track the drug's fate, toxicity, lifetime, and metabolism within the body. Such analyses are performed thoughout phase 1 through phase 3 clinical trials, and are necessary for the ultimate approval of drugs by regulatory agencies. The use of carbon-14 allows the drug structure to be labeled without changing its actual chemical structure, which is critical to avoid changing the behavior of the material. Unfortunately, the preparation of many carbon-14 labeled materials involves a long synthesis with radioactive material, limiting access to these materials in the timely fashion often needed by the pharmaceutical industry. The project here exploits two significant discoveries emerging from the Arndtsen (McGill) and Gauthier (Merck) groups in the past year, which demonstrate the ability of metal catalysts to mediate the exchange of covalent bonds in organic compounds. These will be used to develop a new and efficient new way to access carbon-14 radiolabeled drugs: via the direct exchange of carbon-14 into carboxylic acids on already prepared pharmaceutical candidates. Overall, the process would offer a versatile method to create carbon-14 labeled pharmaceuticals, and has significant potential for commercial impact in Merck's ability to clinically validate drugs.