posted on 2019-01-15, 09:38authored byFernando 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.
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
2017-03-18
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/