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

Abstract

Signal Amplification By Reversible Exchange (SABRE) is an inexpensive, fast, and even continuous hyperpolarization technique that uses para-hydrogen as hyperpolarization source. However, current SABRE faces a number of stumbling blocks for translation to biochemical and clinical settings. Difficulties include inefficient polarization in in water, relatively short lived 1H-polarization, and relatively limited substrate scope. Here we use a water soluble polarization transfer catalyst to hyperpolarize nitrogen-15 in a variety of molecules with SABRE-SHEATH (SABRE in Shield Enables Alignment Transfer to Heteronuclei). This strategy works in pure H2O or D2O solutions, on substrates that could not be hyperpolarized in traditional 1H-SABRE experiments, and we record 15N T1 relaxation times of up to 2 min.

Hyperpolarizing Concentrated Metronidazole 15NO2 Group over Six Chemical Bonds with More than 15 % Polarization and a 20 Minute Lifetime

“…[49] Moreover,w eh ave recently reported the preparation of pure (i.e.,c atalyst-free) HP metronidazole solutions [36] as well as heterogeneous 15 NS ABRE-SHEATH [50] and 15 NS ABRE-SHEATH HP metronidazole in aqueous media, [51] thereby potentially enabling the preparation of biologically compatible HP MNZ-15 N 3 injectable formulation(s). [49] Moreover,w eh ave recently reported the preparation of pure (i.e.,c atalyst-free) HP metronidazole solutions [36] as well as heterogeneous 15 NS ABRE-SHEATH [50] and 15 NS ABRE-SHEATH HP metronidazole in aqueous media, [51] thereby potentially enabling the preparation of biologically compatible HP MNZ-15 N 3 injectable formulation(s).…”

Signal Amplification by Reversible Exchange (SABRE): From Discovery to Diagnosis

“…[68,69] Thep re-catalyst [IrCl-(COD)(IDEG)] (7)showed most promise and gave up to 42fold 1 H-enhancement at 7Tacross anumber of substrates and circa 1000-fold 15 N-enhancement at 7T for 15 N-pyridine; however, catalyst removal would still be necessary to create abiocompatible bolus for in vivo injection. [70] …”

Heterogeneous Microtesla SABRE Enhancement of 15N NMR Signals

“…support particle size and catalyst surface loading, in addition to those parameters listed farther above), and the fact that enhancements of the same order were observed for the homogeneous catalyst under the same conditions, much larger 15 N enhancements are anticipated to result from ongoing work. The catalyst described here also has the potential for future modifications to render its hyperpolarization in aqueous media, [55–57] which is highly synergistic with recent demonstrations of 15 N SABRE-SHEATH in an aqueous medium [58] and would ultimately pave the way to production of pure (from catalyst) 15 N hyperpolarized biomolecules in aqueous media for biomedical use. Indeed, our efforts will be directed not only toward improving enhancements via such experimental optimization, but also preparation of biologically relevant agents (including the targeting of other nuclei), as well as agent separation and use (and catalyst re-use) for various biological/biomedical applications.…”