Parahydrogen-Induced Polarization of 14N Nuclei.

Hyperpolarization techniques provide a dramatic increase in sensitivity of nuclear magnetic resonance spectroscopy and imaging. In spite of the outstanding progress in solution-state hyperpolarization of spin-1/2 nuclei, hyperpolarization of quadrupolar nuclei remains challenging. Here, hyperpolarization of quadrupolar 14N nuclei with natural isotopic abundance of >99 % is demonstrated. This is achieved via pairwise addition of parahydrogen to tetraalkylammonium salts with vinyl or allyl unsaturated moieties followed by a subsequent polarization transfer from 1H to 14N nuclei at high magnetic field using PH-INEPT or PH-INEPT+ radiofrequency pulse sequence. Catalyst screening identified water-soluble rhodium complex [Rh(P(m-C6H4SO3Na)3)3Cl] as the most efficient catalyst for hyperpolarization of the substrates under study, providing up to 1.3 % and up to 6.6 % 1H polarization in the cases of vinyl and allyl precursors, respectively. The performance of PH-INEPT and PH-INEPT+ pulse sequences was optimized with respect to interpulse delays, and the resultant experimental dependences were in good agreement with simulations. As a result, 14N NMR signal enhancement of up to 760-fold at 7.05 T (corresponding to 0.15 % 14N polarization) was obtained.

Through-Space Multinuclear Magnetic Resonance Signal Enhancement Induced by Parahydrogen and Radiofrequency Amplification by Stimulated Emission of Radiation.

Hyperpolarized (i.e., polarized far beyond the thermal equilibrium) nuclear spins can result in the radiofrequency amplification by stimulated emission of radiation (RASER) effect. Here, we show the utility of RASER to amplify nuclear magnetic resonance (NMR) signals of solute and solvent molecules in the liquid state. Specifically, parahydrogen-induced RASER was used to spontaneously enhance nuclear spin polarization of protons and heteronuclei (here 19F and 31P) in a wide range of molecules. The magnitude of the effect correlates with the T1 relaxation time of the target nuclear spins. A series of control experiments validate the through-space dipolar mechanism of the RASER-assisted polarization transfer between the parahydrogen-polarized compound and to-be-hyperpolarized nuclei of the target molecule. Frequency-selective saturation of the RASER-active resonances was used to control the RASER and the amplitude of spontaneous polarization transfer. Spin dynamics simulations support our experimental RASER studies. The enhanced NMR sensitivity may benefit various NMR applications such as mixture analysis, metabolomics, and structure determination.

Synthesis and 15 N NMR Signal Amplification by Reversible Exchange of [15 N]Dalfampridine at Microtesla Magnetic Fields.

Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare 15 N-labeled [15 N]dalfampridine (4-amino[15 N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE-SHEATH technique) with up to 2.0 % 15 N polarization. The 7-hour-long activation of SABRE pre-catalyst [Ir(IMes)(COD)Cl] in the presence of [15 N]dalfampridine can be remedied by the use of pyridine co-ligand for catalyst activation while retaining the 15 N polarization levels of [15 N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on 15 N polarization levels of free and equatorial catalyst-bound [15 N]dalfampridine were investigated. Moreover, we studied 15 N polarization build-up and decay at magnetic field of less than 0.04 µT as well as 15 N polarization decay at the Earth's magnetic field and at 1.4 T.

15 N NMR Hyperpolarization of Radiosensitizing Antibiotic Nimorazole by Reversible Parahydrogen Exchange in Microtesla Magnetic Fields.

Nimorazole belongs to the imidazole-based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15 N3 ]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next-generation MRI-LINAC systems. Herein, we report the first steps to create long-lasting (for tens of minutes) hyperpolarized state on three 15 N sites of [15 N3 ]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000-fold at 1.4 T (corresponding to P15N of 3.2 %) by 15 N-15 N spin-relayed SABRE-SHEATH hyperpolarization technique, relying on simultaneous exchange of [15 N3 ]nimorazole and parahydrogen on polarization transfer Ir-IMes catalyst. The presented results pave the way to efficient spin-relayed SABRE-SHEATH hyperpolarization of a wide range of imidazole-based antibiotics and chemotherapeutics.