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Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy

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journal contribution
posted on 15.01.2019, 09:38 by Fernando Fernandez Diaz-Rullo, Francesco Zamberlan, Ryan E. Mewis, Marianna Fekete, Lionel Broche, Lesley A. Cheyne, Sergio Dall'Angelo, Simon B. Duckett, Dana Dawson, Matteo Zanda
Hyperpolarization enhances the intensity of the NMR signals of a molecule, whose in vivo metabolic fate can be monitored by MRI with higher sensitivity. SABRE is a hyperpolarization technique that could potentially be used to image nitric oxide (NO) production in vivo. This would be very important, because NO dysregulation is involved in several pathologies, including cardiovascular ones. The nitric oxide synthase (NOS) pathway leads to NO production via conversion of L-arginine into L-citrulline. NO is a free radical gas with a short half-life in vivo (≈5 s), therefore direct NO quantification is challenging. An indirect method – based on quantifying conversion of an L-Arg- to L-Cit-derivative by 1H NMR spectroscopy – is herein proposed. A small library of pyridyl containing L-Arg derivatives was designed and synthesised. In vitro tests showed that compounds 4a–j and 11a–c were better or equivalent substrates for the eNOS enzyme (NO2− production = 19–46 μM) than native L-Arg (NO2− production = 25 μM). Enzymatic conversion of L-Arg to L-Cit derivatives could be monitored by 1H NMR. The maximum hyperpolarization achieved by SABRE reached 870-fold NMR signal enhancement, which opens up exciting future perspectives of using these molecules as hyperpolarized MRI tracers in vivo.

Funding

University of Aberdeen’s Development Trust is gratefully acknowledged for a PhD studentship to F.F.D.-R. S.B.D. would like to thank the Wellcome Trust (grant 92506 and 098335) for funding. F.Z. thanks ‘5 per mille’ contribution from Universita degli Studi di Ferrara (Italy).

History

School

  • Science

Department

  • Chemistry

Published in

Bioorganic and Medicinal Chemistry

Volume

25

Issue

10

Pages

2730 - 2742

Citation

FERNANDEZ DIAZ-RULLO, F. ... et al, 2017. Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy. Bioorganic and Medicinal Chemistry, 25 (10), pp.2730-2742.

Publisher

Elsevier © The Authors

Version

VoR (Version of Record)

Publisher statement

This work is made available according to the conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) licence. Full details of this licence are available at: http://creativecommons.org/licenses/ by/4.0/

Acceptance date

18/03/2017

Publication date

2017

Notes

This is an Open Access Article. It is published by Elsevier under the Creative Commons Attribution 4.0 International Licence (CC BY). Full details of this licence are available at: http://creativecommons.org/licenses/by/4.0/

ISSN

0968-0896

Language

en