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  1. Abstract

    We report dissolution Dynamic Nuclear Polarization (d‐DNP) of [15N3]metronidazole ([15N3]MNZ) for the first time. Metronidazole is a clinically approved antibiotic, which can be potentially employed as a hypoxia‐sensing molecular probe using15N hyperpolarized (HP) nucleus. The DNP process is very efficient for [15N3]MNZ with an exponential build‐up constant of 13.8 min using trityl radical. After dissolution and sample transfer to a nearby 4.7 T Magnetic Resonance Imaging scanner, HP [15N3]MNZ lasted remarkably long with T1values up to 343 s and15N polarizations up to 6.4 %. A time series of HP [15N3]MNZ images was acquired in vitro using a steady state free precession sequence on the15NO2peak. The signal lasted over 13 min with notably long T2of 20.5 s. HP [15N3]MNZ was injected in the tail vein of a healthy rat, and dynamic spectroscopy was performed over the rat brain. The in vivo HP15N signals persisted over 70 s, demonstrating an unprecedented opportunity for in vivo studies.

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  2. Abstract

    Hyperpolarized orthohydrogen (o‐H2) is a frequent product of parahydrogen‐based hyperpolarization approaches like signal amplification by reversible exchange (SABRE), where the hyperpolarizedo‐H2signal is usually absorptive. We describe a novel manifestation of this effect wherein large antiphaseo‐H2signals are observed, with1H enhancements up to ≈500‐fold (effective polarizationPH≈1.6 %). This anomalous effect is attained only when using an intact heterogeneous catalyst constructed using a metal–organic framework (MOF) and is qualitatively independent of substrate nature. This seemingly paradoxical observation is analogous to the “partial negative line” (PNL) effect recently explained in the context of Parahydrogen Induced Polarization (PHIP) by Ivanov and co‐workers. The two‐spin order of theo‐H2resonance is manifested by a two‐fold higher Rabi frequency, and the lifetime of the antiphase HPo‐H2resonance is extended by several‐fold.

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  3. Abstract

    The feasibility of Carbon‐13 Radiofrequency (RF) Amplification by Stimulated Emission of Radiation (C‐13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1‐13C]acetate. Hyperpolarized ethyl [1‐13C]acetate was prepared via pairwise addition of parahydrogen to vinyl [1‐13C]acetate and polarization transfer from nascent parahydrogen‐derived protons to the carbon‐13 nucleus via magnetic field cycling yielding C‐13 nuclear spin polarization of approximately 6 %. RASER signals were detected from samples with concentration ranging from 0.12 to 1 M concentration using a non‐cryogenic 1.4T NMR spectrometer equipped with a radio‐frequency detection coil with a quality factor (Q) of 32 without any modifications. C‐13 RASER signals were observed for several minutes on a single bolus of hyperpolarized substrate to achieve 21 mHz NMR linewidths. The feasibility of creating long‐lasting C‐13 RASER on biomolecular carriers opens a wide range of new opportunities for the rapidly expanding field of C‐13 magnetic resonance hyperpolarization.

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  4. Abstract

    We report on the utility of Radiofrequency Amplification by Stimulated Emission Radiation (RASER) for background‐free proton detection of hyperpolarized biomolecules. We performed hyperpolarization of ≈0.3 M ethyl acetate via pairwise parahydrogen addition to vinyl acetate. A proton NMR signal with signal‐to‐noise ratio exceeding 100 000 was detected without radio‐frequency excitation at the clinically relevant magnetic field of 1.4 T using a standard (non‐cryogenic) inductive detector with quality factor ofQ=68. No proton background signal was observed from protonated solvent (methanol) or other added co‐solvents such as ethanol, water or bovine serum. Moreover, we demonstrate RASER detection without radio‐frequency excitation of a bolus of hyperpolarized contrast agent in biological fluid. Completely background‐free proton detection of hyperpolarized contrast agents in biological media paves the way to new applications in the areas of high‐resolution NMR spectroscopy and in vivo spectroscopy and imaging.

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  5. Abstract

    Demonstration of parahydrogen‐induced polarization effects in hydrogenations catalyzed by heterogeneous catalysts instead of metal complexes in a homogeneous solution has opened an entirely new dimension for parahydrogen‐based research, demonstrating its applicability not only for the production of catalyst‐free hyperpolarized liquids and gases and long‐lived non‐equilibrium spin states for potential biomedical applications, but also for addressing challenges of modern fundamental and industrial catalysis including advanced mechanistic studies of catalytic reactions and operando NMR and MRI of reactors. This essay summarizes the progress achieved in this field by highlighting the research contributed to it by our colleague and friend Kirill V. Kovtunov whose scientific career ended unexpectedly and tragically at the age of 37. His role in this research was certainly crucial, further enhanced by a vast network of his contacts and collaborations at the national and international level.

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  6. Abstract

    Parahydrogen-induced polarization of13C nuclei by side-arm hydrogenation (PHIP-SAH) for [1-13C]acetate and [1-13C]pyruvate esters with application of PH-INEPT-type pulse sequences for1H to13C polarization transfer is reported, and its efficiency is compared with that of polarization transfer based on magnetic field cycling (MFC). The pulse-sequence transfer approach may have its merits in some applications because the entire hyperpolarization procedure is implemented directly in an NMR or MRI instrument, whereas MFC requires a controlled field variation at low magnetic fields. Optimization of the PH-INEPT-type transfer sequences resulted in13C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1-13C]pyruvate and ethyl [1-13C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for1H to13C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1-13C]pyruvate and ethyl [1-13C]acetate, respectively). Nevertheless, a significant13C NMR signal enhancement with respect to thermal polarization allowed us to perform13C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications.

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  7. Abstract

    Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE‐SHEATH) is investigated to achieve rapid hyperpolarization of13C1spins of [1‐13C]pyruvate, using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co‐ligation of DMSO and H2O. Order‐unity13C (>50 %) polarization of catalyst‐bound [1‐13C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1‐13C]pyruvate at lower temperatures. On the catalyst bound pyruvate, 39 % polarization is measured using a 1.4 T NMR spectrometer, and extrapolated to >50 % at the end of build‐up in situ. The highest measured polarization of a 30‐mM pyruvate sample, including free and bound pyruvate is 13 % when using 20 mM DMSO and 0.5 M water in CD3OD. Efficient13C polarization is also enabled by favorable relaxation dynamics in sub‐microtesla magnetic fields, as indicated by fast polarization buildup rates compared to theT1spin‐relaxation rates (e. g., ∼0.2 s−1versus ∼0.1 s−1, respectively, for a 6 mM catalyst‐[1‐13C]pyruvate sample). Finally, the catalyst‐bound hyperpolarized [1‐13C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water, paving the way to future biomedical applications of hyperpolarized [1‐13C]pyruvate produced via comparatively fast and simple SABRE‐SHEATH‐based approaches.

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  8. Abstract

    Hyperpolarization is a technique that can increase nuclear spin polarization with the corresponding gains in nuclear magnetic resonance (NMR) signals by 4–8 orders of magnitude. When this process is applied to biologically relevant samples, the hyperpolarized molecules can be used as exogenous magnetic resonance imaging (MRI) contrast agents. A technique called spin‐exchange optical pumping (SEOP) can be applied to hyperpolarize noble gases such as129Xe. Techniques based on hyperpolarized129Xe are poised to revolutionize clinical lung imaging, offering a non‐ionizing, high‐contrast alternative to computed tomography (CT) imaging and conventional proton MRI. Moreover, CT and conventional proton MRI report on lung tissue structure but provide little functional information. On the other hand, when a subject breathes hyperpolarized129Xe gas, functional lung images reporting on lung ventilation, perfusion and diffusion with 3D readout can be obtained in seconds. In this Review, the physics of SEOP is discussed and the different production modalities are explained in the context of their clinical application. We also briefly compare SEOP to other hyperpolarization methods and conclude this paper with the outlook for biomedical applications of hyperpolarized129Xe to lung imaging and beyond.

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  9. Abstract

    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 prepare15N‐labeled [15N]dalfampridine (4‐amino[15N]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 %15N polarization. The 7‐hour‐long activation of SABRE pre‐catalyst [Ir(IMes)(COD)Cl] in the presence of [15N]dalfampridine can be remedied by the use of pyridine co‐ligand for catalyst activation while retaining the15N polarization levels of [15N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on15N polarization levels of free and equatorial catalyst‐bound [15N]dalfampridine were investigated. Moreover, we studied15N polarization build‐up and decay at magnetic field of less than 0.04 μT as well as15N polarization decay at the Earth's magnetic field and at 1.4 T.

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  10. Abstract

    Magnetic resonance imaging of [1‐13C]hyperpolarized carboxylates (most notably, [1‐13C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of1H and13C hyperpolarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties using heterogeneous hydrogenation of corresponding vinyl, allyl and propargyl precursors in isotopically unlabeled and 1‐13C‐enriched forms with parahydrogen over Rh/TiO2catalysts in methanol‐d4and in D2O. The maximum obtained1H polarization was 0.6±0.2 % (for propyl acetate in CD3OD), while the highest13C polarization was 0.10±0.03 % (for ethyl acetate in CD3OD). Hyperpolarization of acetate esters surpassed that of pyruvates, while esters with a triple carbon‐carbon bond in unsaturated alcoholic moiety were less efficient as parahydrogen‐induced polarization precursors than esters with a double bond. Among the compounds studied, the maximum1H and13C NMR signal intensities were observed for propyl acetate. Ethyl acetate yielded slightly less intense NMR signals which were dramatically greater than those of other esters under study.

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