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

Fernandez Diaz-Rullo, Fernando, Zamberlan, Francesco, Mewis, Ryan E., Fekete, Marianna, Broche, Lionel, Cheyne, Lesley A., Dall'Angelo, Sergio, Duckett, Simon B., Dawson, Dana and Zanda, Matteo (2017) Synthesis and hyperpolarisation of eNOS substrates for quantification of NO production by 1H NMR spectroscopy. Bioorganic & Medicinal Chemistry, 25 (10). pp. 2730-2742. ISSN 0968-0896

Full content URL: http://doi.org/10.1016/j.bmc.2017.03.041

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Abstract

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.

Keywords:NMR, hyperpolarisation, Enzymes, Organic synthesis, bioimaging
Subjects:F Physical Sciences > F100 Chemistry
F Physical Sciences > F110 Applied Chemistry
F Physical Sciences > F160 Organic Chemistry
F Physical Sciences > F165 Biomolecular Chemistry
F Physical Sciences > F163 Bio-organic Chemistry
Divisions:College of Science > School of Chemistry
ID Code:30368
Deposited On:01 Feb 2018 09:26

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