title: A perspective on tritium versus carbon-14: ensuring optimal label selection in pharmaceutical research and development.
abstract: Tritium ((3) H) and carbon-14 ((14) C) labels applied in pharmaceutical research and development each offer their own distinctive advantages and disadvantages coupled with benefits and risks. The advantages of (3) H 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 (14) C offer certain analytical benefits and less potential for label loss. Although (3) H 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 (14) C, which is a more conservative approach. To challenge this '(14) C-by-default' approach, pharmaceutical agents with strategically selected (3) H-labeling positions based on non-labeled metabolism data have been successfully implemented and evaluated for (3) H loss. From in-house results, the long term success of projects clearly would benefit from a thorough, objective, and balanced assessment regarding label selection ((3) H or (14) C). 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.
authors.affiliation: Novartis Institute of BioMedical Research, Forum 1, Novartis Campus, 4056, Basel, Switzerland.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Krauser
mesh_terms: D002250:Carbon Radioisotopes / Q000737:chemistry; D055808:Drug Discovery / Q000379:methods*; D007553:Isotope Labeling / Q000379:methods*; D014316:Tritium / Q000737:chemistry*
chemical_list: D002250:Carbon Radioisotopes; D014316:Tritium
keywords: 14C; 3H; carbon-14; isotope; label selection; metabolic stability; metabolic switching; pharmaceutical research and development; radiolabel; tritiated water; tritium