Deuterium‐ and Tritium‐Labelled Compounds: Applications in the Life Sciences

Abstract

Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium ( H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described.

Efficient Access to Deuterated and Tritiated Nucleobase Pharmaceuticals and Oligonucleotides using Hydrogen‐Isotope Exchange

“…[1] More recently,R NA interference has emerged as an experimental tool to inhibit the expression of genes and gave birth to,r espectively,a ntisense oligonucleotides [2] and small interfering RNA( siRNA), [3] which are under intensive studies as high potential therapeutic agents. [7] In the case of oligonucleotides, the synthetic access to SILS is particularly problematic because of their complexity and relative instability.U pt o now,t he nucleobase hydrogen-isotope labelling is mainly achieved by multistep synthesis starting from precursors such as halogen, ketone,o ra ldehyde derivatives followed by, respectively,c atalytic dehalogenation using D 2 /T 2 gas [8] or reduction with labelled reagents [9] (NaBD 4 or LiAlT 4 for instance). [5] Indeed, tritiated analogues of drug candidates,are essential tools for investigating the in vivo fate of substances within absorption, distribution, metabolism and excretion (ADME) studies.…”

New trends and applications in cyanation isotope chemistry

“…Already examples of syntheses proving their usefulness in 14 C or 11 C isotope chemistry applications exist, and therefore it is realistic to forecast that these methods will further flourish in the future. Furthermore, the possibility of starting with a complex carboxylic acid‐containing molecule and ending up with the same 14 C‐containing molecule via a 1‐pot sequence gives hope that a renaissance in carbon‐14 labelling similar to that spawned by the hydrogen isotope exchange reaction in tritium‐labelling might be possible.…”

“…One of the major challenges for 14 C‐labelling is in obtaining the right precursors for introducing the marker moiety. While the hydrogen isotope exchange reaction has overcome this problem by simply using the target molecule and introducing the label by exchange of hydrogen with a tritium or deuterium atom, it remains a challenge in carbon‐synthesis chemistry. One approach to addressing this starting material issue was first reported by Taran et al in 2010 .…”

Evaluation of a P,N‐ligated iridium(I) catalyst in hydrogen isotope exchange reactions of aryl and heteroaryl compounds

“…In consequence, those HIE methods facilitated a possibility to overcome metabolic stability issues associated with earlier tritiation methods . Thus, today, tritium tracers are widely used for ADME‐profiling of new drug candidates but also as a discovery tool for photoaffinity labelling and for radioligand, protein, and covalent binding assays. In particular, Kerr's catalysts 2 and 3 are widely applied for mild and selective ortho ‐labelling using a broad range of directing groups such as ketones, amides, esters, primary sulfonamides, and several heterocycles .…”