A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development(1-6). Such studies are performed in vivo and in vitro at various stages of the development process-ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials-to elucidate a drug molecule's metabolic profile and to assess its toxicity(2). Radiolabelled compounds, typically those that contain C-14 or H-3 isotopes, are one of the most powerful and widely deployed diagnostics for these studies(4,5). The introduction of radiolabels using synthetic chemistry enables the direct tracing of the drug molecule without substantially altering its structure or function. The ubiquity of C-H bonds in drugs and the relative ease and low cost associated with tritium (H-3) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process(2,4,6). Here we describe an iron-catalysed method for the direct H-3 labelling of pharmaceuticals by hydrogen isotope exchange, using tritium gas as the source of the radioisotope. The site selectivity of the iron catalyst is orthogonal to currently used iridium catalysts and allows isotopic labelling of complementary positions in drug molecules, providing a new diagnostic tool in drug development.
