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The signal amplification by reversible exchange process (SABRE) enhances NMR signals by unlocking hidden polarization in parahydrogen through interactions with to-be-hyperpolarized substrate molecules when both are transiently bound to an Ir-based organometallic catalyst. Recent efforts focus on optimizing polarization transfer from parahydrogen-derived hydride ligands to the substrate in SABRE. However, this requires quantitative information on ligand exchange rates, which common NMR techniques struggle to provide. Here, we introduce an experimental spin order transfer sequence, with readout occurring at 15 N nuclei directly interacting with the catalyst. Enhanced 15 N NMR signals overcome sensitivity challenges, encoding substrate dissociation rates. This methodology enables robust data fitting to ligand exchange models, yielding substrate dissociation rate constants with higher precision than classical 1D and 2D 1 H NMR approaches. This refinement improves the accuracy of key activation enthalpy ΔH ‡ and entropy ΔS ‡ estimates. Furthermore, the higher chemical shift dispersion provided by enhanced 15 N NMR reveals the kinetics of substrate dissociation for acetonitrile and metronidazole, previously inaccessible via 1 H NMR due to small chemical shift differences between free and Ir-bound substrates. The presented approach can be successfully applied not only to isotopically enriched substrates but also to compounds with natural abundance of the to-be-hyperpolarized heteronuclei., Competing Interests: Competing interests: E.Y.C. declares a stake of ownership in XeUS Technologies LTD and Vizma Life Sciences. E.Y.C. serves on the Scientific Advisory Board (SAB) of Vizma Life Sciences. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Proton-hyperpolarized contrast agents are attractive because they can be imaged on virtually any clinical MRI scanner, which is typically equipped to scan only protons rather than heteronuclei ( i.e. , anything besides protons, e.g. , 13 C, 15 N, 129 Xe, 23 Na, etc .). Even though the lifetime of the proton spin hyperpolarization is only a few seconds, it is sufficient for inhalation and scanning of proton-hyperpolarized gas media. We demonstrate the utility of producing hyperpolarized propane gas via heterogeneous parahydrogen-induced polarization for the purpose of ventilation imaging in an excised rabbit lung model. The magnetization of protons in hyperpolarized propane gas is similar to that of tissue water protons, making it possible to rapidly perform lung ventilation imaging with a 0.35 T clinical MRI scanner. Here, we demonstrate the feasibility of rapid (2 s) lung ventilation MRI in excised rabbit lungs using hyperpolarized propane gas with a 1 × 1 mm 2 pixel size using a 50 mm slice thickness, and a 1.7 × 1.7 mm 2 pixel size using a 9 mm slice thickness.

Radio Amplification by Stimulated Emission of Radiation (RASER) is a phenomenon observed during nuclear magnetic resonance (NMR) experiments with strongly negatively polarized systems. This phenomenon may be utilized for the production of very narrow NMR lines, background-free NMR spectroscopy, and excitation-free sensing of chemical transformations. Recently, novel methods of producing RASER by ParaHydrogen-Induced Polarization (PHIP) were introduced. Here, we show that pairwise addition of parahydrogen to various propargylic compounds induces RASER activity of other protons beyond those chemically introduced in the reaction. In high-field PHIP, negative polarization initiating RASER is transferred via intramolecular cross-relaxation. When parahydrogen is added in Earth's field followed by adiabatic transfer to a high field, RASER activity of other protons is induced via both J-couplings and cross-relaxation. This through-bond and through-space induction of RASER holds potential for the ongoing development and expansion of RASER applications and can potentially enhance spectral resolution in two-dimensional NMR spectroscopy techniques., (© 2024. The Author(s).)

NMR spectroscopy studies using parahydrogen-induced polarization have previously established the existence of the pairwise hydrogen addition route in the hydrogenation of unsaturated hydrocarbons over heterogeneous catalysts, including those based on rhodium (Rh 0 ). This pathway requires the incorporation of both hydrogen atoms from one hydrogen molecule to the same product molecule. However, the underlying mechanism for such pairwise hydrogen addition must be better understood. The involvement of carbon, either in the form of carbonaceous deposits on the surface of a catalyst or as a metal carbide phase, is known to modify catalytic properties significantly and thus could also affect the pairwise hydrogen addition route. Here, we explored carbon's role by studying the hydrogenation of propene and propyne with parahydrogen on a Rh 2 C catalyst and comparing the results with those for a Rh 0 /C catalyst obtained from Rh 2 C via H 2 pretreatment. While the catalysts Rh 2 C and Rh 0 /C differ notably in the rate of conversion of parahydrogen to normal hydrogen as well as in terms of hydrogenation activity, our findings suggest that the carbide phase does not play a significant role in the pairwise H 2 addition route on rhodium catalysts., (© 2024 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

Kinetic studies are vital for gathering mechanistic insights into heterogeneously catalyzed hydrogenation of unsaturated organic compounds (olefins), where the Horiuti-Polanyi mechanism is ubiquitous on metal catalysts. While this mechanism envisions nonpairwise H 2 addition due to the rapid scrambling of surface hydride (H*) species, a pairwise H 2 addition is experimentally encountered, rationalized here based on density functional theory (DFT) simulations for the ethene (C 2 H 4 ) hydrogenation catalyzed by two-dimensional (2D) MXene Mo 2 C(0001) surface and compared to Rh(111) surface. Results show that ethyl (C 2 H 5 *) hydrogenation is the rate-determining step (RDS) on Mo 2 C(0001), yet C 2 H 5 * formation is the RDS on Rh(111), which features a higher reaction rate and contribution from pairwise H 2 addition compared to 2D-Mo 2 C(0001). This qualitatively agrees with the experimental results for propene hydrogenation with parahydrogen over 2D-Mo 2 C 1- x MXene and Rh/TiO 2 . However, DFT results imply that pairwise selectivity should be negligible owing to the facile H* diffusion on both surfaces, not affected by H* nor C 2 H 4 * coverages. DFT results also rule out the Eley-Rideal mechanism appreciably contributing to pairwise addition. The measurable contribution of the pairwise hydrogenation pathway operating concurrently with the dominant nonpairwise one is proposed to be due to the dynamic site blocking at higher adsorbate coverages or another mechanism that would drastically limit the diffusion of H* adatoms., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

This study reveals that, when two hydrogen atoms are produced on the surface of a catalyst (e. g., a metal nanoparticle) upon dissociation of a parahydrogen molecule, their initial nuclear spin correlation can propagate in a branching-chain fashion as they diffuse and combine with random H atoms to produce H 2 molecules, which subsequently dissociate. This process leads to a gradual dilution of the non-equilibrium nuclear spin order, but the number of involved H atoms that share the spin order becomes larger. These conclusions, confirmed by the spin density matrix calculations, may be relevant in the context of parahydrogen-induced polarization (PHIP) in heterogeneous hydrogenations catalyzed by supported metal catalysts, the observation of which apparently contradicts the accepted non-pairwise mechanism of the addition of hydrogen to an unsaturated substrate over such catalysts. The potential consequences of the reported findings are discussed in the context of PHIP effects and beyond., (© 2024 Wiley-VCH GmbH.)

NMR hyperpolarization dramatically improves the detection sensitivity of magnetic resonance through the increase in nuclear spin polarization. Because of the sensitivity increase by several orders of magnitude, additional applications have been unlocked, including imaging of gases in physiologically relevant conditions. Hyperpolarized 129 Xe gas recently received FDA approval as the first inhalable gaseous MRI contrast agent for clinical functional lung imaging of a wide range of pulmonary diseases. However, production and utilization of hyperpolarized 129 Xe gas faces a number of translational challenges including the high cost and complexity of contrast agent production and imaging using proton-only (i.e., conventional) clinical MRI scanners, which are typically not suited to scan 129 Xe nuclei. As a solution to circumvent the translational challenges of hyperpolarized 129 Xe, we have recently demonstrated the feasibility of a simple and cheap process for production of proton-hyperpolarized propane gas contrast agent using ultralow-cost disposable production equipment and demonstrated the feasibility of lung ventilation imaging using hyperpolarized propane gas in excised pig lungs. However, previous pilot studies have concluded that the hyperpolarized state of propane gas decays very fast with an exponential decay T 1 constant of ∼0.8 s at 1 bar (physiologically relevant pressure); moreover, the previously reported production rates were too slow for potential clinical utilization. Here, we investigate the feasibility of high-capacity production of hyperpolarized butane gas via heterogeneous parahydrogen-induced polarization using Rh nanoparticle-based catalyst utilizing butene gas as a precursor for parahydrogen pairwise addition. We demonstrate a remarkable result: the lifetime of the hyperpolarized state can be nearly doubled compared to that of propane ( T 1 of ∼1.6 s and long-lived spin-state T S of ∼3.8 s at clinically relevant 1 bar pressure). Moreover, we demonstrate a production speed of up to 0.7 standard liters of hyperpolarized gas per second. These two synergistic developments pave the way to biomedical utilization of proton -hyperpolarized gas media for ventilation imaging. Indeed, here we demonstrate the feasibility of phantom imaging of hyperpolarized butane gas in Tedlar bags and also the feasibility of subsecond 2D ventilation gas imaging in excised rabbit lungs with 1.6 × 1.6 mm 2 in-plane resolution using a clinical MRI scanner. The demonstrated results have the potential to revolutionize functional pulmonary imaging with a simple and inexpensive on-demand production of proton -hyperpolarized gas contrast media, followed by visualization on virtually any MRI scanner, including emerging bedside low-field MRI scanner technology., Competing Interests: The authors declare the following competing financial interest(s): E.Y.C. and B.M.G. declare a stake of ownership in XeUS Technologies LTD. E.Y.C. serves on the Scientific Advisory Board (SAB) and declares a stake of ownership in Vizma Life Sciences., (© 2024 The Authors. Co-published by Nanjing University and American Chemical Society.)

Large signal enhancements can be obtained for NMR analytes using the process of nuclear spin hyperpolarization. Organometallic complexes that bind parahydrogen can themselves become hyperpolarized. Moreover, if parahydrogen and a to-be-hyperpolarized analyte undergo chemical exchange with the organometallic complex it is possible to catalytically sensitize the detection of the analyte via hyperpolarization transfer through spin-spin coupling in this organometallic complex. This process is called Signal Amplification By Reversible Exchange (SABRE). Signal intensity gains of several orders of magnitude can thus be created for various compounds in seconds. The chemical exchange processes play a defining role in controlling the efficiency of SABRE because the lifetime of the complex must match the spin-spin couplings. Here, we show how analyte dissociation rates in the key model substrates pyridine (the simplest six-membered heterocycle), 4-aminopyridine (a drug), and nicotinamide (an essential vitamin biomolecule) can be examined. This is achieved for the most widely employed SABRE motif that is based on IrIMes-derived catalysts by 1 H 1D and 2D exchange NMR spectroscopy techniques. Several kinetic models are evaluated for their accuracy and simplicity. By incorporating variable temperature analysis, the data yields key enthalpies and entropies of activation that are critical for understanding the underlying SABRE catalyst properties and subsequently optimizing behavior through rational chemical design. While several studies of chemical exchange in SABRE have been reported, this work also aims to establish a toolkit on how to quantify chemical exchange in SABRE and ensure that data can be compared reliably.

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 14 N 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 1 H to 14 N nuclei at high magnetic field using PH-INEPT or PH-INEPT+ radiofrequency pulse sequence. Catalyst screening identified water-soluble rhodium complex [Rh(P(m-C 6 H 4 SO 3 Na) 3 ) 3 Cl] as the most efficient catalyst for hyperpolarization of the substrates under study, providing up to 1.3 % and up to 6.6 % 1 H 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, 14 N NMR signal enhancement of up to 760-fold at 7.05 T (corresponding to 0.15 % 14 N polarization) was obtained., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Metronidazole is a prospective hyperpolarized MRI contrast agent with potential hypoxia sensing utility for applications in cancer, stroke, neurodegenerative diseases, etc. We demonstrate a pilot procedure for production of ∼30 mM hyperpolarized [ 15 N 3 ]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three 15 N sites achieved in less than 2 min. The 15 N polarization T 1 of ∼12 min is reported for the 15 NO 2 group at the clinically relevant field of 1.4 T in the aqueous phase, demonstrating a remarkably long lifetime of the hyperpolarized state. The produced aqueous solution of [ 15 N 3 ]metronidazole that contained only ∼100 μM of residual Ir was deemed biocompatible via validation through the MTT colorimetric test for assessing cell metabolic activity using human embryotic kidney HEK293T cells. This low-cost and ultrafast hyperpolarization procedure represents a major advance for the production of a biocompatible HP [ 15 N 3 ]metronidazole (and potentially other hyperpolarized drugs) formulation for MRI sensing applications.

Hyperpolarized 129 Xe gas was FDA-approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP 129 Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of 129 Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton ( 1 H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch-mode production of proton-hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1-liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub-second 2D MRI with up to 2×2 mm 2 in-plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner., (© 2024 Wiley-VCH GmbH.)

We present an integrated, open-source device for parahydrogen-based hyperpolarization processes in the microtesla field regime with a cost of components of less than $7000. The device is designed to produce a batch of 13 C and 15 N hyperpolarized (HP) compounds via hydrogenative or non-hydrogenative parahydrogen-induced polarization methods that employ microtesla magnetic fields for efficient polarization transfer of parahydrogen-derived spin order to X-nuclei (e.g., 13 C and 15 N). The apparatus employs a layered structure (reminiscent of a Russian doll "Matryoshka") that includes a nonmagnetic variable-temperature sample chamber, a microtesla magnetic field coil (operating in the range of 0.02-75 microtesla), a three-layered mu-metal shield (to attenuate the ambient magnetic field), and a magnetic shield degaussing coil placed in the overall device enclosure. The gas-handling manifold allows for parahydrogen-gas flow and pressure control (up to 9.2 bar of total parahydrogen pressure). The sample temperature can be varied either using a water bath or a PID-controlled heat exchanger in the range from -12 to 80 °C. This benchtop device measures 62 cm (length) × 47 cm (width) × 47 cm (height), weighs 30 kg, and requires only connections to a high-pressure parahydrogen gas supply and a single 110/220 VAC power source. The utility of the device has been demonstrated using an example of parahydrogen pairwise addition to form HP ethyl [1- 13 C]acetate ( P 13C = 7%, [c] = 1 M). Moreover, the Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) technique was employed to demonstrate efficient hyperpolarization of 13 C and 15 N spins in a wide range of biologically relevant molecules, including [1- 13 C]pyruvate ( P 13C = 14%, [c] = 27 mM), [1- 13 C]-α-ketoglutarate ( P 13C = 17%), [1- 13 C]ketoisocaproate ( P 13C = 18%), [ 15 N 3 ]metronidazole ( P 15N = 13%, [c] = 20 mM), and others. While the vast majority of the utility studies have been performed in standard 5 mm NMR tubes, the sample chamber of the device can accommodate a wide range of sample container sizes and geometries of up to 1 L sample volume. The device establishes an integrated, simple, inexpensive, and versatile equipment gateway needed to facilitate parahydrogen-based hyperpolarization experiments ranging from basic science to preclinical applications; indeed, detailed technical drawings and a bill of materials are provided to support the ready translation of this design to other laboratories.

In this work we achieve a significant overpopulation (P LLS ≈1%) of the long-lived spin state (LLS) of methylene protons in 2-bromoethan( 2 H)ol (BrEtOD) obtained in a reaction between ethylene with non-equilibrium nuclear spin order and bromine water. Given all protons in ethylene are magnetically equivalent, its nuclear states are classified into nuclear spin isomers (NSIM) with total spin I = 2,1,0. Addition of parahydrogen to acetylene produces ethylene with a population of only those NSIMs with I = 1,0. As a result of the reaction with bromine water the non-equilibrium spin order of ethylene is partly transferred to the singlet LLS involving the two methylene groups of BrEtOD. The 1 H NMR signal enhancement (SE≈200) obtained as a result of the LLS readout is approximately equal to the SE of the hyperpolarized BrEtOD obtained with a single π/4 pulse. The LLS relaxation time (T LLS ) was shown to be approximately 40 s (≈8T 1 ) in the argon-bubbled sample., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Symmetric molecules exist as distinct nuclear spin isomers (NSIMs). A deeper understanding of their properties, including interconversion of different NSIMs, requires efficient techniques for NSIM enrichment. In this work, selective hydrogenation of acetylene with parahydrogen (p-H 2 ) was used to achieve the enrichment of ethylene NSIMs and to study their equilibration processes. The effect of the stereoselectivity of H 2 addition to acetylene on the imbalance of ethylene NSIMs was experimentally demonstrated by using three different heterogeneous catalysts (an immobilized Ir complex and two supported Pd catalysts). The interconversion of NSIMs with time during ethylene storage was studied using NMR spectroscopy by reacting ethylene with bromine water, which rendered the p-H 2 -derived protons in the produced 2-bromoethan( 2 H)ol (BrEtOD) magnetically inequivalent, thereby revealing the non-equilibrium nuclear spin order of ethylene. A thorough analysis of the shape and transformation of the 1 H NMR spectra of hyperpolarized BrEtOD allowed us to reveal the initial distribution of produced ethylene NSIMs and their equilibration processes. Comparison of the results obtained with three different catalysts was key to properly attributing the derived characteristic time constants to different ethylene NSIM interconversion processes: ∼3-6 s for interconversion between NSIMs with the same inversion symmetry ( i.e. , within g or u manifolds) and ∼1700-2200 s between NSIMs with different inversion symmetries ( i.e. , between g and u manifolds).

13 C hyperpolarized pyruvate is an emerging MRI contrast agent for sensing molecular events in cancer and other diseases with aberrant metabolic pathways. This metabolic contrast agent can be produced via several hyperpolarization techniques. Despite remarkable success in research settings, widespread clinical adoption faces substantial roadblocks because the current sensing technology utilized to sense this contrast agent requires the excitation of 13 C nuclear spins that also need to be synchronized with MRI field gradient pulses. Here, we demonstrate sensing of hyperpolarized allyl [1- 13 C]pyruvate via the stimulated emission of radiation that mitigates the requirements currently blocking broader adoption. Specifically, 13 C Radiofrequency Amplification by Stimulated Emission of Radiation ( 13 C RASER) was obtained after pairwise addition of parahydrogen to a pyruvate precursor, detected in a commercial inductive detector with a quality factor ( Q ) of 32 for sample concentrations as low as 0.125 M with 13 C polarization of 4%. Moreover, parahydrogen-induced polarization allowed for the preparation of a mixture of ketone and hemiketal forms of hyperpolarized allyl [1- 13 C]pyruvate, which are separated by 10 ppm in 13 C NMR spectra. This is a good model system to study the simultaneous 13 C RASER signals of multiple 13 C species. This system models the metabolic production of hyperpolarized [1- 13 C]lactate from hyperpolarized [1- 13 C]pyruvate, which has a similar chemical shift difference. Our results show that 13 C RASER signals can be obtained from both species simultaneously when the emission threshold is exceeded for both species. On the other hand, when the emission threshold is exceeded only for one of the hyperpolarized species, 13 C stimulated emission is confined to this species only, therefore enabling the background-free detection of individual hyperpolarized 13 C signals. The reported results pave the way to novel sensing approaches of 13 C hyperpolarized pyruvate, potentially unlocking hyperpolarized 13 C MRI on virtually any MRI system─an attractive vision for the future molecular imaging and diagnostics.

Hyperpolarized magnetic resonance imaging (MRI) contrast agents are revolutionizing the field of biomedical imaging. Hyperpolarized Xe-129 was recently FDA approved as an inhalable MRI contrast agent for functional lung imaging sensing. Despite success in research settings, modern Xe-129 hyperpolarizers are expensive (up to $1M), large, and complex to site and operate. Moreover, Xe-129 sensing requires specialized MRI hardware that is not commonly available on clinical MRI scanners. Here, we demonstrate that proton-hyperpolarized propane gas can be produced on demand using a disposable, hand-held, clinical-scale hyperpolarizer via parahydrogen-induced polarization, which relies on parahydrogen as a source of hyperpolarization. The device consists of a heterogeneous catalytic reactor connected to a gas mixture storage can containing pressurized hyperpolarization precursors: propylene and parahydrogen (10 bar total pressure). Once the built-in flow valve of the storage can is actuated, the precursors are ejected from the can into a reactor, and a stream of hyperpolarized propane gas is ejected from the reactor. Robust operation of the device is demonstrated for producing proton sensing polarization of 1.2% in a wide range of operational pressures and gas flow rates. We demonstrate that the propylene/parahydrogen gas mixture can retain potency for days in the storage can with a monoexponential decay time constant of 6.0 ± 0.5 days, which is limited by the lifetime of the parahydrogen singlet spin state in the storage container. The utility of the produced sensing agent is demonstrated for phantom imaging on a 3 T clinical MRI scanner located 100 miles from the agent/device preparation site and also for ventilation imaging of excised pig lungs using a 0.35 T clinical MRI scanner. The cost of the device components is less than $35, which we envision can be reduced to less than $5 for mass-scale production. The hyperpolarizer device can be reused, recycled, or disposed.

Immobilized [Ir(COD)Cl] 2 -Linker/TiO 2 catalysts with linkers containing Py, P(Ph) 2 and N(CH 3 ) 2 functional groups were prepared. The catalysts were tested via propene hydrogenation with parahydrogen in a temperature range from 40 °C to 120 °C which was monitored via NMR. The catalytic behavior of [Ir(COD)Cl] 2 -Linker/TiO 2 is explained on the basis of quantitative and qualitative XPS data analysis performed for the catalysts before and after the reaction at 120 °C. It is shown that the temperature dependence of propene conversion and the enhancement of the NMR signal are explained via a combination of the stabilities of both the linker and immobilized [Ir(COD)Cl] 2 complex. It is demonstrated that the N(CH 3 ) 2 -linker is the most stable at the surface of TiO 2 under used reaction conditions. As a result, only this sample shows a rise in the enhancement of the NMR signal in the 100-120 °C temperature range.

We show that catalyst-free aqueous solutions of hyperpolarized [1- 13 C]succinate can be produced using parahydrogen-induced polarization (PHIP) and a combination of homogeneous and heterogeneous catalytic hydrogenation reactions. We generate hyperpolarized [1- 13 C]fumarate via PHIP using para-enriched hydrogen gas with a homogeneous ruthenium catalyst, and subsequently remove the toxic catalyst and reaction side products via a purification procedure. Following this, we perform a second hydrogenation reaction using normal hydrogen gas to convert the fumarate into succinate using a solid Pd/Al 2 O 3 catalyst. This inexpensive polarization protocol has a turnover time of a few minutes, and represents a major advance for in vivo applications of [1- 13 C]succinate as a hyperpolarized contrast agent.

Magnetic resonance techniques are successfully utilized in a broad range of scientific disciplines and in various practical applications, with medical magnetic resonance imaging being the most widely known example. Currently, both fundamental and applied magnetic resonance are enjoying a major boost owing to the rapidly developing field of spin hyperpolarization. Hyperpolarization techniques are able to enhance signal intensities in magnetic resonance by several orders of magnitude, and thus to largely overcome its major disadvantage of relatively low sensitivity. This provides new impetus for existing applications of magnetic resonance and opens the gates to exciting new possibilities. In this review, we provide a unified picture of the many methods and techniques that fall under the umbrella term "hyperpolarization" but are currently seldom perceived as integral parts of the same field. Specifically, before delving into the individual techniques, we provide a detailed analysis of the underlying principles of spin hyperpolarization. We attempt to uncover and classify the origins of hyperpolarization, to establish its sources and the specific mechanisms that enable the flow of polarization from a source to the target spins. We then give a more detailed analysis of individual hyperpolarization techniques: the mechanisms by which they work, fundamental and technical requirements, characteristic applications, unresolved issues, and possible future directions. We are seeing a continuous growth of activity in the field of spin hyperpolarization, and we expect the field to flourish as new and improved hyperpolarization techniques are implemented. Some key areas for development are in prolonging polarization lifetimes, making hyperpolarization techniques more generally applicable to chemical/biological systems, reducing the technical and equipment requirements, and creating more efficient excitation and detection schemes. We hope this review will facilitate the sharing of knowledge between subfields within the broad topic of hyperpolarization, to help overcome existing challenges in magnetic resonance and enable novel applications.

The present work investigates the potential for enhancing the NMR signals of DNA nucleobases by parahydrogen-based hyperpolarization. Signal amplification by reversible exchange (SABRE) and SABRE in Shield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) of selected DNA nucleobases is demonstrated with the enhancement ( ε ) of 1 H, 15 N, and/or 13 C spins in 3-methyladenine, cytosine, and 6-O-guanine. Solutions of the standard SABRE homogenous catalyst Ir(1,5-cyclooctadeine)(1,3-bis(2,4,6-trimethylphenyl)imidazolium)Cl ("IrIMes") and a given nucleobase in deuterated ethanol/water solutions yielded low 1 H ε values (≤10), likely reflecting weak catalyst binding. However, we achieved natural-abundance enhancement of 15 N signals for 3-methyladenine of ~3300 and ~1900 for the imidazole ring nitrogen atoms. 1 H and 15 N 3-methyladenine studies revealed that methylation of adenine affords preferential binding of the imidazole ring over the pyrimidine ring. Interestingly, signal enhancements ( ε ~240) of both 15 N atoms for doubly labelled cytosine reveal the preferential binding of specific tautomer(s), thus giving insight into the matching of polarization-transfer and tautomerization time scales. 13 C enhancements of up to nearly 50-fold were also obtained for this cytosine isotopomer. These efforts may enable the future investigation of processes underlying cellular function and/or dysfunction, including how DNA nucleobase tautomerization influences mismatching in base-pairing.

Magnetic resonance imaging (MRI) provides unique information about the internal structure and function of living organisms in a non-invasive way. The use of conventional proton MRI for the observation of real-time metabolism is hampered by the dominant signals of water and fat, which are abundant in living organisms. Heteronuclear MRI in conjunction with the hyperpolarization methods does not encounter this issue. In this work, we polarized 15 N nuclei of [ 15 N 1 ]fampridine (a drug used for the treatment of multiple sclerosis) to the level of 4% in nuclear magnetic resonance (NMR) experiments and 0.7% in MRI studies using spin-lock-induced crossing combined with signal amplification by reversible exchange. Consequently, three-dimensional 15 N MRI of the hyperpolarized 15 N-labeled drug was acquired in 0.1 s with a signal-to-noise ratio of 70. In addition, the NMR signal enhancements for 15 N-enriched fampridine and fampridine with a natural abundance of 15 N nuclei were compared and an explanation for their difference was proposed.

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 19 F and 31 P) in a wide range of molecules. The magnitude of the effect correlates with the T 1 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.

In this work the mechanism of methylenecyclobutane hydrogenation over titania-supported Rh, Pt and Pd catalysts was investigated using parahydrogen-induced polarization (PHIP) technique. It was found that methylenecyclobutane hydrogenation leads to formation of a mixture of reaction products including cyclic (1-methylcyclobutene, methylcyclobutane), linear (1-pentene, cis-2-pentene, trans-2-pentene, pentane) and branched (isoprene, 2-methyl-1-butene, 2-methyl-2-butene, isopentane) compounds. Generally, at lower temperatures (150-350 °C) the major reaction product was methylcyclobutane while higher temperature of 450 °C favors the formation of branched products isoprene, 2-methyl-1-butene and 2-methyl-2-butene. PHIP effects were detected for all reaction products except methylenecyclobutane isomers 1-methylcyclobutene and isoprene implying that the corresponding compounds can incorporate two atoms from the same parahydrogen molecule in a pairwise manner in the course of the reaction in particular positions. The mechanisms were proposed for the formation of these products based on PHIP results., (© 2022 Wiley-VCH GmbH.)

Typical magnetic resonance experiments are routinely limited by weak signal responses. In some cases, the low intrinsic sensitivity can be alleviated by the implementation of hyperpolarization technologies. Dissolution-dynamic nuclear polarization offers a means of hyperpolarizing small molecules. Hyperpolarized water is employed in several dynamic nuclear polarization studies, and hence accurate and rapid quantification of the 1 H polarization level is of utmost importance. The solid-state nuclear magnetic resonance spectrum of water acquired under dissolution-dynamic nuclear polarization conditions has revealed lineshapes which become asymmetric at high levels of 1 H polarization, which is an interesting fundamental problem in itself, but also complicates data interpretation and can prevent correct estimations of polarization levels achieved. In previous studies, attempts to simulate the 1 H spectral lineshape of water as a function of the 1 H polarization led to significant disagreement with the experimental results. Here we propose and demonstrate that such simulations, and therefore polarization quantification, can be implemented accurately, in particular by taking into account the detector dead time during 1 H signal acquisition that can lead to severe spectral distortions. Based on these findings, we employed an echo-based radiofrequency pulse sequence to achieve distortion-free 1 H spectra of hyperpolarized water, and adequate simulations of these echo-based spectra were implemented to extract the absolute 1 H polarization level from the hyperpolarized water signal only, thus alleviating the need for lengthy and insensitive measurements of thermal equilibrium signals.

Nuclear magnetic resonance (NMR) has become a universal method for biochemical and biomedical studies, including metabolomics, proteomics, and magnetic resonance imaging (MRI). By increasing the signal of selected molecules, the hyperpolarization of nuclear spin has expanded the reach of NMR and MRI even further (e.g. hyperpolarized solid-state NMR and metabolic imaging in vivo). Parahydrogen (pH 2 ) offers a fast and cost-efficient way to achieve hyperpolarization, and the last decade has seen extensive advances, including the synthesis of new tracers, catalysts, and transfer methods. The portfolio of hyperpolarized molecules now includes amino acids, which are of great interest for many applications. Here, we provide an overview of the current literature and developments in the hyperpolarization of amino acids and peptides., (© 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

The hyperpolarization of nuclear spins is a game-changing technology that enables hitherto inaccessible applications for magnetic resonance in chemistry and biomedicine. Despite significant advances and discoveries in the past, however, the quest to establish efficient and effective hyperpolarization methods continues. Here, we describe a new method that combines the advantages of direct parahydrogenation, high polarization ( P ), fast reaction, and low cost with the broad applicability of polarization transfer via proton exchange. We identified the system propargyl alcohol + pH 2 → allyl alcohol to yield 1 H polarization in excess of P ≈ 13% by using only 50% enriched pH 2 at a pressure of ≈1 bar. The polarization was then successfully relayed via proton exchange from allyl alcohol to various target molecules. The polarizations of water and alcohols (as target molecules) approached P ≈ 1% even at high molar concentrations of 100 mM. Lactate, glucose, and pyruvic acid were also polarized, but to a lesser extent. Several potential improvements of the methodology are discussed. Thus, the parahydrogen-induced hyperpolarization relayed via proton exchange (PHIP-X) is a promising approach to polarize numerous molecules which participate in proton exchange and support new applications for magnetic resonance.

Parahydrogen-induced polarization with heterogeneous catalysts (HET-PHIP) has been a subject of extensive research in the last decade since its first observation in 2007. While NMR signal enhancements obtained with such catalysts are currently below those achieved with transition metal complexes in homogeneous hydrogenations in solution, this relatively new field demonstrates major prospects for a broad range of advanced fundamental and practical applications, from providing catalyst-free hyperpolarized fluids for biomedical magnetic resonance imaging (MRI) to exploring mechanisms of industrially important heterogeneous catalytic processes. This review covers the evolution of the heterogeneous catalysts used for PHIP observation, from metal complexes immobilized on solid supports to bulk metals and single-atom catalysts and discusses the general visions for maximizing the obtained NMR signal enhancements using HET-PHIP. Various practical applications of HET-PHIP, both for catalytic studies and for potential production of hyperpolarized contrast agents for MRI, are described., (© 2021 Wiley-VCH GmbH.)

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high-resolution NMR spectroscopy to real-time metabolic imaging in vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the 13 C and 15 N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T 1 allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low-cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of 15 N nuclei. Although large sensitivity gains are enabled by hyperpolarization, 15 N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of 15 N-labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques., (© 2021 Wiley-VCH GmbH.)

Magnetic resonance imaging of [1- 13 C]hyperpolarized carboxylates (most notably, [1- 13 C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of 1 H and 13 C 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- 13 C-enriched forms with parahydrogen over Rh/TiO 2 catalysts in methanol-d 4 and in D 2 O. The maximum obtained 1 H polarization was 0.6±0.2 % (for propyl acetate in CD 3 OD), while the highest 13 C polarization was 0.10±0.03 % (for ethyl acetate in CD 3 OD). 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 maximum 1 H and 13 C 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., (© 2021 Wiley-VCH GmbH.)

We report on a robust and low-cost parahydrogen generator design employing liquid nitrogen as a coolant. The core of the generator consists of catalyst-filled spiral copper tubing, which can be pressurized to 35 atm. Parahydrogen fraction >48% was obtained at 77 K with three nearly identical generators using paramagnetic hydrated iron oxide catalysts. Parahydrogen quantification was performed on the fly via benchtop NMR spectroscopy to monitor the signal from residual orthohydrogen-parahydrogen is NMR silent. This real-time quantification approach was also used to evaluate catalyst activation at up to 1.0 standard liter per minute flow rate. The reported inexpensive device can be employed for a wide range of studies employing parahydrogen as a source of nuclear spin hyperpolarization. To this end, we demonstrate the utility of this parahydrogen generator for hyperpolarization of concentrated sodium [1- 13 C]pyruvate, a metabolic contrast agent under investigation in numerous clinical trials. The reported pilot optimization of SABRE-SHEATH (signal amplification by reversible exchange-shield enables alignment transfer to heteronuclei) hyperpolarization yielded 13 C signal enhancement of over 14,000-fold at a clinically relevant magnetic field of 1 T corresponding to approximately 1.2% 13 C polarization-if near 100% parahydrogen would have been employed, the reported value would be tripled to 13 C polarization of 3.5%.

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., (© 2021 Wiley-VCH GmbH.)

The selectivity of product formation is strongly correlated with the nature of the catalyst active centers. Therefore, the selective synthesis of active sites with certain structure is a big challenge in modern catalysis. Here synthetic procedures are adopted for the formation of 1% Rh/TiO 2 catalysts with different properties. It is shown that the nature of the precursor used for catalyst preparation is important, and that the use of a solution of rhodium acetate instead of rhodium nitrate leads to the selective formation of butenes during 1,3-butadiene hydrogenation. The use of parahydrogen in the reaction results in the enhancement of NMR signals via parahydrogen-induced polarization (PHIP) for all synthesized catalysts, and this signal enhancement increases with increasing catalyst calcination temperature. This effect is explained by the decoration of rhodium nanoparticles with titania which restricts hydrogen mobility on the surface, leading to the highest reported to date selectivity toward the pairwise hydrogen addition route of 7% for supported metal catalysts.

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., (© 2021 Wiley-VCH GmbH.)

Production of hyperpolarized catalyst-free gases and liquids by heterogeneous hydrogenation with parahydrogen can be useful for various technical as well as biomedical applications, including in vivo studies, investigations of mechanisms of industrially important catalytic processes, enrichment of nuclear spin isomers of polyatomic gases, and more. In this regard, the wide systematic search for heterogeneous catalysts effective in pairwise H 2 addition required for the observation of parahydrogen-induced polarization (PHIP) effects is crucial. Here in this work we demonstrate the competitive advantage of Pd-based bimetallic catalysts for PHIP in heterogeneous hydrogenations (HET-PHIP). The dilution of catalytically active Pd with less active Ag or In atoms provides the formation of atomically dispersed Pd 1 sites on the surface of Pd-based bimetallic catalysts, which are significantly more selective toward pairwise H 2 addition compared to the monometallic Pd. Furthermore, the choice of the dilution metal (Ag or In) has a pronounced effect on the efficiency of bimetallic catalysts in HET-PHIP, as revealed by comparing Pd-Ag and Pd-In bimetallic catalysts., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2021 Dudari B. Burueva et al.)

Parahydrogen-induced polarization of 13 C nuclei by side-arm hydrogenation (PHIP-SAH) for [1- 13 C]acetate and [1- 13 C]pyruvate esters with application of PH-INEPT-type pulse sequences for 1 H to 13 C 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 in 13 C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1- 13 C]pyruvate and ethyl [1- 13 C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for 1 H to 13 C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1- 13 C]pyruvate and ethyl [1- 13 C]acetate, respectively). Nevertheless, a significant 13 C NMR signal enhancement with respect to thermal polarization allowed us to perform 13 C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications.

Many MRI contrast agents formed with the parahydrogen-induced polarization (PHIP) technique exhibit biocompatible profiles. In the context of respiratory imaging with inhalable molecular contrast agents, the development of nonflammable contrast agents would nonetheless be highly beneficial for the biomedical translation of this sensitive, high-throughput and affordable hyperpolarization technique. To this end, we assess the hydrogenation kinetics, the polarization levels and the lifetimes of PHIP hyperpolarized products (acids, ethers and esters) at various degrees of fluorine substitution. The results highlight important trends as a function of molecular structure that are instrumental for the design of new, safe contrast agents for in vivo imaging applications of the PHIP technique, with an emphasis on the highly volatile group of ethers used as inhalable anesthetics., (© 2020 Wiley-VCH GmbH.)

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 N 3 ]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 N 3 ]nimorazole with T 1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000-fold at 1.4 T (corresponding to P 15N of 3.2 %) by 15 N- 15 N spin-relayed SABRE-SHEATH hyperpolarization technique, relying on simultaneous exchange of [ 15 N 3 ]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., (© 2020 Wiley-VCH GmbH.)

Magnetic resonance imaging (MRI) with the use of hyperpolarized gases as contrast agents provides valuable information on lungs structure and function. While the technology of 129 Xe hyperpolarization for clinical MRI research is well developed, it requires the expensive equipment for production and detection of hyperpolarized 129 Xe. Herein we present the 1 H hyperpolarization of diethyl ether vapor that can be imaged on any clinical MRI scanner. 1 H nuclear spin polarization of up to 1.3 % was achieved using heterogeneous hydrogenation of ethyl vinyl ether with parahydrogen over Rh/TiO 2 catalyst. Liquefaction of diethyl ether vapor proceeds with partial preservation of hyperpolarization and prolongs its lifetime by ≈10 times. The proof-of-principle 2D 1 H MRI of hyperpolarized diethyl ether was demonstrated with 0.1×1.1 mm 2 spatial and 120 ms temporal resolution. The long history of use of diethyl ether for anesthesia is expected to facilitate the clinical translation of the presented approach., (© 2020 Wiley-VCH GmbH.)

The reactivity of the frustrated Lewis pair (FLP) (F 5 C 2 ) 3 SnCH 2 P(tBu) 2 (1) was investigated with respect to the activation of elemental hydrogen. The reaction of 1 at elevated hydrogen pressure afforded the intramolecular phosphonium stannate(II) (F 5 C 2 ) 2 SnCH 2 PH(tBu) 2 (3). It was characterized by means of multinuclear NMR spectroscopy and single crystal X-ray diffraction. NMR experiments with the two isotopologues H 2 and D 2 showed it to be formed via an H 2 adduct (F 5 C 2 ) 3 HSnCH 2 PH(tBu) 2 (2) and the subsequent formal reductive elimination of pentafluoroethane; this is supported by DFT calculations. Parahydrogen-induced polarization experiments revealed the formation of a second product of the reaction of 1 with H 2 , [HP(tBu) 2 Me][Sn(C 2 F 5 ) 3 ] (4), in 1 H NMR spectra, whereas 2 was not detected due to its transient nature., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas-phase lifetimes of hyperpolarized 129 Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of 129 Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low-cost and high-throughput preparation of proton-hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by 1 H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas-phase T 1 relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, with T 1 of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long-lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond., (© 2020 Wiley-VCH GmbH.)

Imaging of gases is a major challenge for any modality including MRI. NMR and MRI signals are directly proportional to the nuclear spin density and the degree of alignment of nuclear spins with applied static magnetic field, which is called nuclear spin polarization. The level of nuclear spin polarization is typically very low, i.e., one hundred thousandth of the potential maximum at 1.5 T and a physiologically relevant temperature. As a result, MRI typically focusses on imaging highly concentrated tissue water. Hyperpolarization methods transiently increase nuclear spin polarizations up to unity, yielding corresponding gains in MRI signal level of several orders of magnitude that enable the 3D imaging of dilute biomolecules including gases. Parahydrogen-induced polarization is a fast, highly scalable, and low-cost hyperpolarization technique. The focus of this Minireview is to highlight selected advances in the field of parahydrogen-induced polarization for the production of hyperpolarized compounds, which can be potentially employed as inhalable contrast agents., (© 2020 Wiley-VCH GmbH.)

We demonstrate that heterogeneous/biphasic chemical reactions can be monitored with high spectroscopic resolution using zero-field nuclear magnetic resonance spectroscopy. This is possible because magnetic susceptibility broadening is negligible at ultralow magnetic fields. We show the two-step hydrogenation of dimethyl acetylenedicarboxylate with para-enriched hydrogen gas in conventional glass NMR tubes, as well as in a titanium tube. The low frequency zero-field NMR signals ensure that there is no significant signal attenuation arising from shielding by the electrically conductive sample container. This method paves the way for in situ monitoring of reactions in complex heterogeneous multiphase systems and in reactors made of conductive materials while maintaining resolution and chemical specificity., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

15 N spin-lattice relaxation dynamics in metronidazole- 15 N 3 and metronidazole- 15 N 2 isotopologues are studied for rational design of 15 N-enriched biomolecules for signal amplification by reversible exchange in microtesla fields. 15 N relaxation dynamics mapping reveals the deleterious effects of interactions with the polarization transfer catalyst and a quadrupolar 14 N nucleus within the spin-relayed 15 N- 15 N network.

We present a pilot quality assurance (QA) study of spin-exchange optical pumping (SEOP) performed on two nearly identical second-generation (GEN-2) automated batch-mode clinical-scale 129 Xe hyperpolarizers, each utilizing a convective forced air oven, high-power (~170 W) continuous pump laser irradiation, and xenon-rich gas mixtures (~1.30 atm partial pressure). In one study, the repeatability of SEOP in a 1000 Torr Xe/900 Torr N 2 /100 Torr 4 He (2000 Torr total pressure) gas mixture is evaluated over the course of ~700 gas loading cycles, with negligible decrease in performance during the first ~200 cycles, and with high 129 Xe polarization levels (avg. %P Xe  = 71.7% with standard deviation σ PXe  = 1.5%), build-up rates (avg. γ SEOP  = 0.019 min -1 with standard deviation σ γ  = 0.003 min -1 ) and polarization lifetimes (avg. T 1  = 90.5 min with standard deviation σ T  = 10.3 min) reported at moderate oven temperature of ~70 °C. Although the SEOP cell in this study exhibited a detectable performance decrease after 400 cycles, the cell continued to produce potentially useable HP 129 Xe with %P Xe  = 42.3 ± 0.6% even after nearly 700 refill cycles. The possibility of "regenerating" "dormant" (i.e., not used for an extended period of time) SEOP cells using repeated temperature cycling methods to recover %P Xe is also demonstrated. The quality and consistency of results show significant promise for translation to clinical-scale production of hyperpolarized 129 Xe contrast agents for imaging and bio-sensing applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We present studies of spin-exchange optical pumping (SEOP) using ternary xenon-nitrogen-helium gas mixtures at high xenon partial pressures (up to 1330 Torr partial pressure at loading, out of 2660 Torr total pressure) in a 500-mL volume SEOP cell, using two automated batch-mode clinical-scale 129 Xe hyperpolarizers operating under continuous high-power (~170 W) pump laser irradiation. In this pilot study, we explore SEOP in gas mixtures with up to 45% 4 He content under a wide range of experimental conditions. When an aluminum jacket cooling/heating design was employed (GEN-3 hyperpolarizer), 129 Xe polarization (%P Xe ) of 55.9 ± 0.9% was observed with mono-exponential build-up rate γ SEOP of 0.049 ± 0.001 min -1 for the 4 He-rich mixture (1000 Torr Xe/900 Torr He, 100 Torr N 2 ), compared to %P Xe of 49.3 ± 3.3% at γ SEOP of 0.035 ± 0.004 min -1 for the N 2 -rich gas mixture (1000 Torr Xe/100 Torr He, 900 Torr N 2 ). When forced-air cooling/heating was used (GEN-2 hyperpolarizer), %P Xe of 83.9 ± 2.7% was observed at γ SEOP of 0.045 ± 0.005 min -1 for the 4 He-rich mixture (1000 Torr Xe/900 Torr He, 100 Torr N 2 ), compared to %P Xe of 73.5 ± 1.3% at γ SEOP of 0.028 ± 0.001 min -1 for the N 2 -rich gas mixture (1000 Torr Xe and 1000 Torr N 2 ). Additionally, %P Xe of 72.6 ± 1.4% was observed at a build-up rate γ SEOP of 0.041 ± 0.003 min -1 for a super-high-density 4 He-rich mixture (1330 Torr Xe/1200 Torr 4 He/130 Torr N 2 ), compared to %P Xe  = 56.6 ± 1.3% at a build-up rate of γ SEOP of 0.034 ± 0.002 min -1 for an N 2 -rich mixture (1330 Torr Xe/1330 Torr N 2 ) using forced air cooling/heating. The observed SEOP hyperpolarization performance under these conditions corresponds to %P Xe improvement by a factor of 1.14 ± 0.04 at 1000 Torr Xe density and by up to a factor of 1.28 ± 0.04 at 1330 Torr Xe density at improved SEOP build-up rates by factors of 1.61 ± 0.18 and 1.21 ± 0.11 respectively. Record %P Xe levels have been obtained here: 83.9 ± 2.7% at 1000 Torr Xe partial pressure and 72.6 ± 1.4% at 1330 Torr Xe partial pressure. In addition to improved thermal stability for SEOP, the use of 4 He-rich gas mixtures also reduces the overall density of produced inhalable HP contrast agents; this property may be desirable for HP 129 Xe inhalation by human subjects in clinical settings-especially in populations with heavily impaired lung function. The described approach should enjoy ready application in the production of inhalable 129 Xe contrast agent with near-unity 129 Xe nuclear spin polarization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Among the hyperpolarization techniques geared toward in vivo magnetic resonance imaging, parahydrogen-induced polarization (PHIP) shows promise due to its low cost and fast speed of contrast agent preparation. The synthesis of 13 C-labeled, unsaturated precursors to perform PHIP by side arm hydrogenation has recently opened new possibilities for metabolic imaging owing to the biological compatibility of the reaction products, although the polarization transfer between the parahydrogen-derived protons and the 13 C heteronucleus must yet be better understood, characterized, and eventually optimized. In this realm, a new experimental strategy incorporating pulse-programmable magnetic field sweeping and in situ detection has been developed. The approach is evaluated by measuring the 13 C polarization of ethyl acetate-1- 13 C, i.e ., the product of pairwise addition of parahydrogen to vinyl acetate-1- 13 C, resulting from zero-crossing magnetic field ramps of various durations, amplitudes, and step sizes. The results demonstrate (i) the profound effect these parameters have on the 1 H to 13 C polarization transfer efficiency and (ii) the high reproducibility of the technique.

Parahydrogen-induced polarization (PHIP) is a powerful technique for studying hydrogenation reactions in gas and liquid phases. Pairwise addition of parahydrogen to the hydrogenation substrate imparts nuclear spin order to reaction products, manifested as enhanced 1H NMR signals from the nascent proton sites. Nanoscale metal catalysts immobilized on supports comprise a promising class of catalysts for producing PHIP effects; however, on such catalysts the percentage of substrates undergoing the pairwise addition route-a necessary condition for observing PHIP-is usually low. In this paper, we present a systematic study of several metal catalysts (Rh, Pt, Pd, and Ir) supported on TiO2 in liquid-phase hydrogenation of different prototypical phenylalkynes (phenylacetylene, 1-phenyl-1-propyne, and 3-phenyl-1-propyne) with parahydrogen. Catalyst activity and selectivity were found to be affected by both the nature of the active metal and the percentage of metal loading. It was demonstrated that the optimal catalyst for production of hyperpolarized products is Rh/TiO2 with 4 wt% metal loading, whereas Pd/TiO2 provided the greatest selectivity for semihydrogenation of phenylalkynes. In a study of liquid-phase hydrogenation reaction kinetics, it was shown that reaction order with respect to hydrogen is nearly the same for pairwise and non-pairwise H2 addition-consistent with a similar nature of the catalytically active sites for these reaction pathways.

A robust medium-scale (approximately 3 g) synthetic method for 15 N labeling of pyridine ( 15 N-Py) is reported based on the Zincke reaction. 15 N enrichment in excess of 81% was achieved with approximately 33% yield. 15 N-Py serves as a standard substrate in a wide range of studies employing a hyperpolarization technique for efficient polarization transfer from parahydrogen to heteronuclei; this technique, called SABRE (signal amplification by reversible exchange), employs a simultaneous chemical exchange of parahydrogen and a to-be-hyperpolarized substrate (e.g., pyridine) on metal centers. In studies aimed at the development of hyperpolarized contrast agents for in vivo molecular imaging, pyridine is often employed either as a model substrate (for hyperpolarization technique development, quality assurance, and phantom imaging studies) or as a co-substrate to facilitate more efficient hyperpolarization of a wide range of emerging contrast agents (e.g., nicotinamide). Here, the produced 15 N-Py was used for the feasibility study of spontaneous 15 N hyperpolarization at high magnetic (HF) fields (7 T and 9.4 T) of an NMR spectrometer and an MRI scanner. SABRE hyperpolarization enabled acquisition of 2D MRI imaging of catalyst-bound 15 N-pyridine with 75 × 75 mm 2 field of view (FOV), 32 × 32 matrix size, demonstrating the feasibility of 15 N HF-SABRE molecular imaging with 2.4 × 2.4 mm 2 spatial resolution., (© 2018 John Wiley & Sons, Ltd.)

Signal Amplification by Reversible Exchange (SABRE) is a promising method for NMR signal enhancement and production of hyperpolarized molecules. As nuclear spin relaxation times of heteronuclei are usually much longer than those of protons, SABRE-based hyperpolarization of heteronuclei in molecules is highly important in the context of biomedical applications. In this work, we demonstrate that the SLIC-SABRE technique can be successfully used to hyperpolarize 15 N nuclei in dalfampridine. The high polarization level of ca. 8 % achieved in this work made it possible to acquire 15 N MR images at natural abundance of the 15 N nuclei for the first time., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)