Iron-catalysed tritiation of pharmaceuticals

Abstract

A thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development1,2,3,4,5,6. 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 toxicity2. Radiolabelled compounds, typically those that contain 14C or 3H isotopes, are one of the most powerful and widely deployed diagnostics for these studies4,5. 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 (3H) make it an ideal radioisotope with which to conduct ADME studies early in the drug development process2,4,6. Here we describe an iron-catalysed method for the direct 3H 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.

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Figure 1: Homogeneous transition metal-catalysed hydrogen/tritium exchange using tritium gas.
Figure 2: Fe-catalysed deuterium labelling of representative arenes and heteroarenes.
Figure 3: Fe-catalysed deuterium labelling of drug molecules.
Figure 4: Tritium labelling of drug molecules.

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Acknowledgements

Merck and the Intellectual Property Accelerator Fund at Princeton University are acknowledged for financial support. We thank M. Tudge, I. Mergelsberg, L.-C. Campeau and I. Davies for discussions. We also thank D. Schenk and Y. Liu for assistance in 3H NMR assignments.

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Contributions

R.P.Y. and P.J.C. discovered the iron-catalysed reaction. R.P.Y. performed initial deuterium exchange studies. R.P.Y. and I.P. performed the analysis of deuterium labelled products. I.P. developed and implemented the quantitative 13C NMR protocol for analysis of deuterium labelled products. R.P.Y., D.H. and N.R. performed and analysed tritium-labelling studies. R.P.Y., D.H. and P.J.C. prepared the manuscript.

Corresponding author

Correspondence to Paul J. Chirik.

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Competing interests

The authors have filed a provisional patent application on the composition of the catalyst and its use in radiolabelling of pharmaceuticals.

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This file contains Supplementary Text and Data, Supplementary Figures 1-21 and Supplementary References – see contents page for details. (PDF 13475 kb)

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Pony Yu, R., Hesk, D., Rivera, N. et al. Iron-catalysed tritiation of pharmaceuticals. Nature 529, 195–199 (2016). https://doi.org/10.1038/nature16464

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