Please use this identifier to cite or link to this item: https://apo.ansto.gov.au/dspace/handle/10238/11291
Title: 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
Authors: Murphy, RB
Wyatt, AN
Fraser, BH
Yepuri, NR
Holden, PJ
Wotherspoon, ATL
Darwish, TA
Keywords: Deuteration
Mass spectroscopy
Isotope effects
Kinetics
Synthesis
In vitro
Inflammation
Issue Date: 8-Aug-2019
Publisher: Elsevier B. V.
Citation: Murphy, 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.2019.02.025
Abstract: The 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.
URI: https://doi.org/10.1016/j.aca.2019.02.025
https://apo.ansto.gov.au/dspace/handle/10238/11291
ISSN: 0003-2670
Appears in Collections:Journal Articles

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