Generalizing, Extending, and Maximizing Nitrogen-15 Hyperpolarization Induced by Parahydrogen in Reversible Exchange

Abstract

Signal Amplification by Reversible Exchange (SABRE) is a fast and convenient NMR hyperpolarization method that uses cheap and readily available para-hydrogen as a hyperpolarization source. SABRE can hyperpolarize protons and heteronuclei. Here we focus on the heteronuclear variant introduced as SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) and nitrogen-15 targets in particular. We show that 15N-SABRE works more efficiently and on a wider range of substrates than 1H-SABRE, greatly generalizing the SABRE approach. In addition, we show that nitrogen-15 offers significantly extended T1 times of up to 12 minutes. Long T1 times enable higher hyperpolarization levels but also hold the promise of hyperpolarized molecular imaging for several tens of minutes. Detailed characterization and optimization are presented, leading to nitrogen-15 polarization levels in excess of 10% on several compounds.

Direct Hyperpolarization of Nitrogen-15 in Aqueous Media with Parahydrogen in Reversible Exchange

“…Depending on system composition a linear or exponential dependence of 15 N polarization on the flow rate was reported. 26, 36–37 We conclude the para -hydrogen enrichment in solution is limited by the exchange at the gas-liquid interface.…”

“…The response curves originate from two distinct matching conditions associated with overpopulation in 15 N-α or 15 N-β, giving either positive or negative NMR signal with identical polarization levels. 26 The matching conditions are given by 7 $$B_{\text{evo}}=\pm \frac{J_{\text{HH}}+J_{\text{NH}}/2}{{\gamma }_{\mathrm{H}}-{\gamma }_{\mathrm{N}}}$$where J HH is the hydride-to-hydride J -coupling (~ 10 Hz) and J NH the hydride to 15 N coupling (~ 20 Hz) in ( 1 ).…”

Parahydrogen‐Based Hyperpolarization for Biomedicine

“…[38a, 39] To date, one of the most successful PTC’s is an Iridium based IMes (1,3-bis(2,4,6-trimethylphenyl)-imidazolium) catalyst [Ir(IMes)H 2 Py 2 S] + , which was first introduced by Cowley et al in 2011. [40] …”

“…7)" rend="display" xml:id="FD7">$${\mathrm{normal\omega }}_{\mathrm{normalH}}-{\mathrm{normal\omega }}_{\mathrm{normalS}}\approx 2\mathrm{\pi }J$$ where ω H is the frequency of the hydrides, ω S the frequency of the substrate spins and J is a combination of J -couplings in the PTC that is often dominated by the J -coupling between the two hydride spins ( J HH′ ≈-8Hz). [39d, 46] …”

Long-Lived 13C2 Nuclear Spin States Hyperpolarized by Parahydrogen in Reversible Exchange at Microtesla Fields

“…The presented advances can be translated to biomolecules already shown to be amenable to heteronuclear SABRE hyperpolarization including nicotinamide 20, 46 , in vivo pH sensor imidazole 47 , hypoxia sensor metronidazole 43 and others. 10, 48 While the current work was performed in methanol solutions, recent advances in heterogeneous 49–50 and water-soluble 51–56 SABRE catalysis may lead to in vivo translation of the presented approach for fast hyperpolarization of long-lived 13 C molecular probes.…”