Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Iron-catalysed tritiation of pharmaceuticals

Nature volume 529, pages 195–199 (2016)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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.

References

  1. Lappin, G. & Temple, S. Radiotracers in Drug Development (CRC Press, 2006)

  2. Isin, E. M., Elmore, C. S., Nilsson, G. N., Thompson, R. A. & Weidolf, L. Use of radiolabeled compounds in drug metabolism and pharmacokinetic studies. Chem. Res. Toxicol. 25, 532–542 (2012)

    Article  CAS  Google Scholar 

  3. Marathe, P. H., Shyu, W. C. & Humphreys, W. G. The use of radiolabeled compounds for ADME studies in discovery and exploratory development. Curr. Pharm. Des. 10, 2991–3008 (2004)

    Article  CAS  Google Scholar 

  4. Lockley, W. J. S., McEwen, A. & Cooke, R. Tritium: a coming of age for drug discovery and development ADME studies. J. Labelled Comp. Radiopharm. 55, 235–257 (2012)

    Article  CAS  Google Scholar 

  5. Elmore, C. S. The use of isotopically labeled compounds in drug discovery. Annu. Rep. Med. Chem. 44, 515–534 (2009)

    CAS  Google Scholar 

  6. Voges, R., Heys, J. R. & Moenius, T. Preparation of Compounds Labeled with Tritium and Carbon-14 (John Wiley, 2009)

  7. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54, 2529–2591 (2011)

    Article  CAS  Google Scholar 

  8. Katsnelson, A. Heavy drugs draw heavy interest from pharma backers. Nature Med. 19, 656 (2013)

    Article  CAS  Google Scholar 

  9. Jarman, M. et al. The deuterium isotope effect for the α-hydroxylation of tamoxifen by rat liver microsomes accounts for the reduced genotoxicity of [D5-ethyl]tamoxifen. Carcinogenesis 16, 683–688 (1995)

    Article  CAS  Google Scholar 

  10. Atzrodt, J., Derdau, V., Fey, T. & Zimmermann, J. The renaissance of H/D exchange. Angew. Chem. Int. Edn 46, 7744–7765 (2007)

    Article  CAS  Google Scholar 

  11. Klei, S. R., Golden, J. T., Tilley, T. D. & Bergman, R. G. Iridium-catalyzed H/D exchange into organic compounds in water. J. Am. Chem. Soc. 124, 2092–2093 (2002)

    Article  CAS  Google Scholar 

  12. Ma, S., Villa, G., Thuy-Boun, P. S., Homs, A. & Yu, J.-Q. Palladium-catalyzed ortho-selective C-H deuteration of arenes: evidence for superior reactivity of weakly coordinated palladacycles. Angew. Chem. Int. Edn 53, 734–737 (2014)

    Article  CAS  Google Scholar 

  13. Zhou, J. & Hartwig, J. F. Iridium-catalyzed H/D exchange at vinyl groups without olefin isomerization. Angew. Chem. Int. Edn 47, 5783–5787 (2008)

    Article  CAS  Google Scholar 

  14. Crabtree, R., Felkin, H. & Morris, G. Cationic iridium diolefin complexes as alkene hydrogenation catalysts and isolation of some related hydrido complexes. J. Organomet. Chem. 141, 205–215 (1977)

    Article  CAS  Google Scholar 

  15. Nilsson, G. N. & Kerr, W. J. The development and use of novel iridium complexes as catalysts for ortho-directed hydrogen isotope exchange reactions. J. Labelled Comp. Radiopharm. 53, 662–667 (2010)

    Article  CAS  Google Scholar 

  16. Hesk, D., Das, P. R. & Evans, B. Deuteration of acetanilides and other substituted aromatics using [Ir(COD)(Cy3P)(Py)]PF6 as catalyst. J. Labelled Comp. Radiopharm. 36, 497–502 (1995)

    Article  CAS  Google Scholar 

  17. Lockley, W. J. S. & Heys, J. R. Metal-catalysed hydrogen isotope exchange labelling: a brief overview. J. Labelled Comp. Radiopharm. 53, 635–644 (2010)

    Article  CAS  Google Scholar 

  18. Brown, J. A. et al. The synthesis of highly active iridium(I) complexes and their application in catalytic hydrogen isotope exchange. Adv. Synth. Catal. 356, 3551–3562 (2014)

    Article  CAS  Google Scholar 

  19. Salter, R. The development and use of iridium(I) phosphine systems for ortho-directed hydrogen-isotope exchange. J. Labelled Comp. Radiopharm. 53, 645–657 (2010)

    Article  CAS  Google Scholar 

  20. Danopoulos, A. A., Wright, J. A. & Motherwell, W. B. Molecular N2 complexes of iron stabilised by N-heterocyclic ‘pincer’ dicarbene ligands. Chem. Commun. 784–786 (2005)

  21. Yu, R. P. et al. High-activity iron catalysts for the hydrogenation of hindered, unfunctionalized alkenes. ACS Catal. 2, 1760–1764 (2012)

    Article  CAS  Google Scholar 

  22. Yu, R. P. et al. Catalytic hydrogenation activity and electronic structure determination of bis(arylimidazol-2-ylidene)pyridine cobalt alkyl and hydride complexes. J. Am. Chem. Soc. 135, 13168–13184 (2013)

    Article  CAS  Google Scholar 

  23. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014)

    Article  CAS  Google Scholar 

  24. Taylor, R. D., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014)

    Article  CAS  Google Scholar 

  25. Skaddan, M. B., Yung, C. M. & Bergman, R. G. Stoichiometric and catalytic deuterium and tritium labeling of ‘unactivated’ organic substrates with cationic Ir(III) complexes. Org. Lett. 6, 11–13 (2004)

    Article  CAS  Google Scholar 

  26. Liu, J. K. & Couldwell, W. T. Intra-arterial papaverine infusions for the treatment of cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage. Neurocrit. Care 2, 124–132 (2005)

    Article  Google Scholar 

  27. Coleman, P. J. et al. Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties. ChemMedChem 7, 415–424 (2012)

    Article  CAS  Google Scholar 

  28. Molinaro, C. et al. CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development. J. Org. Chem. 77, 2299–2309 (2012)

    Article  CAS  Google Scholar 

  29. Lischka, P. et al. In vitro and in vivo activities of the novel anticytomegalovirus compound AIC246. Antimicrob. Agents Chemother. 54, 1290–1297 (2010)

    Article  CAS  Google Scholar 

  30. Nagasaki, T. et al. A new practical tritium labelling procedure using sodium borotritide and tetrakis(triphenylphosphine)palladium(0). J. Labelled Comp. Radiopharm. 44, 993–1004 (2001)

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Chemistry, Princeton University, Princeton, 08544, New Jersey, USA

    Renyuan Pony Yu, István Pelczer & Paul J. Chirik

  2. Merck Research Laboratories, Rahway, 07065, New Jersey, USA

    David Hesk & Nelo Rivera

Authors
  1. Renyuan Pony Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Hesk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nelo Rivera
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. István Pelczer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul J. Chirik
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Information

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

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature16464

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing