Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at a-amino sp(3) carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T-2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.
Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds
Loh, Y. Y., Nagao, K., Hoover, A. J., Hesk, D., Rivera, N. R., Colletti, S. L., Davies, I. W., & MacMillan, D. W. C. (2017). Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science, 358(6367), 1182-1187. https://doi.org/10.1126/science.aap9674
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