Recent Developments in Tritium Incorporation for Radiotracer Studies

Abstract

The essential nature of rapid radiotracer synthesis very early in drug discovery programs has driven the need for better and more varied tritium incorporation methods. This review presents a summary of recent advances for tritium introduction via tritiated water, tritium gas, complex tritides, and a range of recently improved tritiation reagents. Access to a wider range of tritiated reagents (for tritioacetylation, tritioformylation, methylation, etc.) and commercial manifolds for the transfer and use of tritium gas is also discussed.

Selective H–D exchange catalysed by aqueous phase and immobilised Pd nanoparticles

“…Furthermore, experiments at extended times in the presence of Pd(DMAP) 4 This suggests that the mode of co-ordination of the DMAP molecules becomes less selective at higher temperatures with perhaps the DMAP adsorbing side-on or face-on to the nanoparticles rather than through the endocyclic N atom.…”

“…Deuterated molecules can also be used in stable isotopic tracer studies for use in GC or LC MS internal standardisation as well as in more specialist applications such as the development of non-linear optical materials [3]. Such labelling also provides a route to obtain analogous tritium labelled molecules for radiotracer studies [4]. Furthermore, using acid catalysed, base catalysed or metal catalysed processes [5], D and T labels can be introduced into organic substrates post-synthetically in contrast to the introduction of most 13 C labels and other isotopically labelled atoms.…”

Using a Tritiated Compound to Elucidate Its Preclinical Metabolic and Excretory Pathways in Vivo: Exploring Tritium Exchange Risk

“…However, in certain instances, 3 H has been used instead of (or in addition to) 14 C to attain in vitro (Guroff et al, 1967;Kler et al, 1992;Linnet, 2004) and in vivo (Prakash et al, 1997;Ehlhardt et al, 1998;Koller-Lucae et al, 1999;Rosenborg et al, 1999;Gray et al, 2001) biotransformation data. Due to the general synthetic ease, low cost, and rapid turnaround of 3 H incorporation (Saljoughian and Williams, 2000), such high specific activity compounds are desirable when radiolabeled material is needed quickly to answer particular metabolism-related questions during drug discovery or development. Although a compound's 14 C atom may become separated from the substructure retained by the majority of metabolites because of its incorporation at a metabolically labile site (Chasseaud et al, 1974;Hawkins et al, 1977;Larsson and Lund, 1981), there is no concern of its passive chemical exchange leading to nonradiolabeled compound and/or metabolites.…”

Radionuclides in drug development

“…On the one hand, the final compound is tritiated directly and, on the other hand, 3 H is incorporated upon the synthesis of a precursor [24]. In such a case, it is necessary to synthesize an appropriate precursor to be reacted with 3 H 2 gas or another source of 3 H. The most common route is an aromatic halogenation of a precursor molecule (typically using N-iodosuccinimide and trifluoroacetic acid) followed by reduction with Pd/C and 3 H 2 gas to yield the final 3 H-containing Q3 compound [25]. The method allowing properly functionalized molecules to incorporate 3 H 2 gas directly into the molecule without any modification is called the 'Ir-catalyzed hydrogen isotope exchange' (HIE) developed by Heys [26] and Hesk et al [27].…”