A perspective on tritium versus carbon-14: ensuring optimal label selection in pharmaceutical research and development

Tritium (H-3) and carbon-14 (C-14) labels applied in pharmaceutical research and development each offer their own distinctive advantages and disadvantages coupled with benefits and risks. The advantages of H-3 have a higher specific activity, shorter half-life that allows more manageable waste remediation, lower material costs, and often more direct synthetic routes. The advantages of C-14 offer certain analytical benefits and less potential for label loss. Although H-3 labels offer several advantages, they might be overlooked as a viable option because of the concerns about its drawbacks. A main drawback often challenged is metabolic liability. These drawbacks, in some cases, might be overstated leading to underutilization of a perfectly viable option. As a consequence, label selection may automatically default to C-14, which is a more conservative approach. To challenge this C-14-by-default' approach, pharmaceutical agents with strategically selected H-3-labeling positions based on non-labeled metabolism data have been successfully implemented and evaluated for H-3 loss. From in-house results, the long term success of projects clearly would benefit from a thorough, objective, and balanced assessment regarding label selection (H-3 or C-14). This assessment should be based on available project information and scientific knowledge. Important considerations are project applicability (preclinical and clinical phases), synthetic feasibility, costs, and timelines.