Syntheses of isotope-labeled tobacco-specific nitrosamines and their metabolites

We report here on the syntheses of three deuterium-labeled tobacco-specific nitrosamines namely [2,4,5,6-d₄]nitroso-nornicotine([2,4,5,6-d ₄]NNN), 4-(methylnitrosamino)-1-(3-[2,4,5,6-d₄]pyridyl)-1- butanone ([2,4,5,6-d₄]NNK), and 4-(methyl-nitrosamino)-1-(3-[2,4,5,6- d₄]pyridyl)-1-butanol ([2,4,5,6-d₄]NNAL). A metabolite of NNK and myosmine, 4-hydroxy-1-(3-[2,4,5,6-d₄]pyridyl)-1-butanone, was also synthesized. The synthetic strategy reported here is similar to that reported in the literature for the preparation of corresponding unlabeled compounds. The commercially available [2,4,5,6-d₄]ethylnicotinate was used as starting material. During the course of these syntheses [2,4,5,6-d ₄]myosmme and [2,4,5,6-d₄]nornicotine were obtained as stable intermediates. These isotope-labeled compounds are useful internal standards for quantification of TSNA and their metabolites in smokers in molecular epidemiological studies.