A rapid MS/MS method to assess the deuterium kinetic isotope effect and associated improvement in the metabolic stability of deuterated biological and pharmacological molecules as applied to an imaging agent

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dc.contributor.authorMurphy, RBen_AU
dc.contributor.authorWyatt, ANen_AU
dc.contributor.authorFraser, BHen_AU
dc.contributor.authorYepuri, NRen_AU
dc.contributor.authorHolden, PJen_AU
dc.contributor.authorWotherspoon, ATLen_AU
dc.contributor.authorDarwish, TAen_AU
dc.date.accessioned2021-08-10T01:22:58Zen_AU
dc.date.available2021-08-10T01:22:58Zen_AU
dc.date.issued2019-08-08en_AU
dc.date.statistics2021-08-08en_AU
dc.description.abstractThe deuterium kinetic isotope effect has been known for a period of 40 years, but it is only relatively recently that new drug entities (NDEs) incorporating deuterium demonstrating beneficial pharmacokinetics, pharmacodynamics, and toxicology have arrived to market. Determination of the precise location to deuterate and subsequently any evaluation for a kinetic isotope effect (KIE) is challenging. Typically, such an evaluation would be performed in an in vitro metabolic assay (e.g. liver microsomes) in separate reaction media for both the deuterated and non-deuterated analogues. Here, we have devised an approach whereby we incubate a 1:1 ratio of both the deuterated and protio-form of an imaging agent together in the same liver microsomal assay and determine the relative rate of consumption of both moieties, based upon specific MS-MS transitions unique to both molecules without the need for liquid chromatography-mass spectrometry (LC-MS) separation and quantification. Any deviation of the ratio of the MS transitions from the initial starting point indicated an observable KIE. A site specific deuteration of PBR111, a neuroinflammation imaging agent, was chosen for a proof-of-concept study. Based upon prior mechanistic knowledge of PBR111, two locations were selected for deuteration; an active and inactive site, to corroborate that there was no significant KIE for the inactive site and confirm the efficacy of the developed methodology. Crown Copyright © 2019 Published by Elsevier B.V.en_AU
dc.identifier.citationMurphy, R. B., Wyatt, N. A., Fraser, B. H., Yepuri, N. R., Holden, P. J., Wotherspoon, A. T. L., & Darwish, T. A. (2019). A rapid MS/MS method to assess the deuterium kinetic isotope effect and associated improvement in the metabolic stability of deuterated biological and pharmacological molecules as applied to an imaging agent. Analytica Chimica Acta, 1064, 65-70. doi:10.1016/j.aca.2019.02.025en_AU
dc.identifier.issn0003-2670en_AU
dc.identifier.journaltitleAnalytica Chimica Actaen_AU
dc.identifier.pagination65-70en_AU
dc.identifier.urihttps://doi.org/10.1016/j.aca.2019.02.025en_AU
dc.identifier.urihttps://apo.ansto.gov.au/dspace/handle/10238/11291en_AU
dc.identifier.volume1064en_AU
dc.language.isoenen_AU
dc.publisherElsevier B. V.en_AU
dc.subjectDeuterationen_AU
dc.subjectMass spectroscopyen_AU
dc.subjectIsotope effectsen_AU
dc.subjectKineticsen_AU
dc.subjectSynthesisen_AU
dc.subjectIn vitroen_AU
dc.subjectInflammationen_AU
dc.titleA rapid MS/MS method to assess the deuterium kinetic isotope effect and associated improvement in the metabolic stability of deuterated biological and pharmacological molecules as applied to an imaging agenten_AU
dc.typeJournal Articleen_AU
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