¹⁵N Hyperpolarization by Reversible Exchange Using SABRE-SHEATH

Abstract

NMR signal amplification by reversible exchange (SABRE) is a NMR hyperpolarization technique that enables nuclear spin polarization enhancement of molecules via concurrent chemical exchange of a target substrate and parahydrogen (the source of spin order) on an iridium catalyst. Recently, we demonstrated that conducting SABRE in microtesla fields provided by a magnetic shield enables up to 10% 15N-polarization (Theis, T.; et al. J. Am. Chem. Soc.2015, 137, 1404). Hyperpolarization on 15N (and heteronuclei in general) may be advantageous because of the long-lived nature of the hyperpolarization on 15N relative to the short-lived hyperpolarization of protons conventionally hyperpolarized by SABRE, in addition to wider chemical shift dispersion and absence of background signal. Here we show that these unprecedented polarization levels enable 15N magnetic resonance imaging. We also present a theoretical model for the hyperpolarization transfer to heteronuclei, and detail key parameters that should be optimized for efficient 15N-hyperpolarization. The effects of parahydrogen pressure, flow rate, sample temperature, catalyst-to-substrate ratio, relaxation time (T1), and reversible oxygen quenching are studied on a test system of 15N-pyridine in methanol-d4. Moreover, we demonstrate the first proof-of-principle 13C-hyperpolarization using this method. This simple hyperpolarization scheme only requires access to parahydrogen and a magnetic shield, and it provides large enough signal gains to enable one of the first 15N images (2 × 2 mm2 resolution). Importantly, this method enables hyperpolarization of molecular sites with NMR T1 relaxation times suitable for biomedical imaging and spectroscopy.

Heterogeneous Microtesla SABRE Enhancement of 15N NMR Signals

“…Whereas both 15 N NMR spectra show clear hyperpolarized 15 N resonances assigned to free 15 N-py substrate, only the solution containing the homogeneous catalysts exhibits additional peaks in the 240–270 ppm range—peaks that are attributed to equatorially and axially bound py, respectively. [30] If the enhanced signal in Figures 2d/3a were obtained from leached homogeneous catalyst moieties, then one would expect to see corresponding peaks from catalyst-bound substrate; however, the peaks from substrate bound to the heterogeneous catalyst particles are too weak (and/or too broadened) to manifest significantly in the observed spectra (consistent with previous 1 H results with microscale HET-SABRE particles). [22] While ε 15N ~100 fold is ~10 times lower than that using homogeneous variant of this catalyst (when taking into account para -H 2 enrichment), [32] no temperature or field optimization was performed here.…”

SABRE Hyperpolarization of Bipyridine Stabilized Ir-Complex at High, Low and Ultralow Magnetic Fields

“…High field experiments and ultralow field SABRE [25] experiments were carried out on a Bruker AVANCE III HD NMR spectrometer with B 0 = 9.4 T. Enhancement factors were obtained in respect to corresponding thermal signal at 9.4 T for 15 N and at 7 T for 1 H. All spectra shown in the main text were recorded with a single scan.…”

“…The computation shows that most efficient polarization transfer is expected at a field ≈0.3 μT. The method of 15 N-SABRE at ultra-low magnetic fields has already been proposed [25] and is called SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) as it requires preparation of SABRE polarization inside a magnetic shield box (or μ-box). The principal scheme for the SABRE-SHEATH experiment is shown in Figure 2A and it consist of three stages: (stage 1) SABRE polarization is prepared inside a μ-box at a field of the order of 1 μT, then (stage 2) the sample is transferred to the detection field B 0 = 9.4 T and, finally, (stage 3) after a 90° RF-pulse the FID is measured.…”

Delivering strong 1 H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

“…This route shows great potential for enhancing both analytical NMR and clinical diagnosis in the future (17)(18)(19)(20)(21)(22). SABRE does not change the chemical identity of the agent it hyperpolarizes but equilibrates polarization between p-H 2 and the selected agent through binding to an iridium center (23).…”