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Hydrogen isotopes in the race for new drugs

Isotopic labeling remains essential for monitoring the in vivo fate of drug candidates. CEA-Joliot researchers have developed high-performance deuterium and tritium labelling techniques.

Published on 28 September 2020

Testing drug candidates is a long, costly process and only 10% of the molecules tested are ultimately commercialized. One way to optimize this process is to identify early on the candidates with the best efficacy and minimal toxicity by evaluating their behaviour in vivo. To do this, researchers "tag" these molecules, i.e. "stick" a label on them, without denaturing them, in order to follow their path and their effects in the organism. One technique consists of substituting certain hydrogen (H) atoms of the molecule with its isotopes, deuterium D (stable) or tritium T (radioactive). 

The scientific challenge taken up by CEA-Joliot researchers is to carry out this exchange (H in D or T) in a rapid and environmentally friendly way, without going through the formation of intermediates of synthesis, thus limiting the production of radioactive waste. "We have developed a highly efficient tritium isotope labeling method using an iridium pre-catalyst," explains Grégory Pieters, a chemist at CEA-Joliot. The catalysts act like scissors to cut the H-C bonds and allow the exchange of the hydrogen atom by the tritium. This method differs from existing techniques by its ease of implementation, because this pre-catalyst, which is commercially available, is stable in air and therefore easy to handle. In addition, its field of application is vast because extremely complex and fragile active ingredients have been radiolabelled. Scientists have also been able to achieve record levels of tritium incorporation into the molecule. 

In addition, these same researchers have obtained more fundamental results concerning deuterium labeling. "We have shown, for the first time, that the addition of organic ligands to the surface of a heterogeneous ruthenium catalyst makes it possible to promote C-H activation reactions over other undesired reactions in the context of labelling complex molecules (H-D exchange)," explains Grégory Pieters. This new approach, potentially applicable to a large number of heterogeneous catalysts, could lead to the discovery of new reactions facilitating access to products of pharmaceutical interest.

Frédéric Joliot Institute for Life Sciences - CEA Paris-Saclay
​French National Research Institute for Agriculture, Food and Environment (Inrae)
​LPCNO, Toulouse University
​ICMMO, Orsay
​Laboratoire de Chimie de Coordination (LCC), CNRS, Toulouse

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