Inherent loss of parahydrogen-induced polarization for systems with magnetically equivalent nuclei in magnetic field cycling experiments.

In the present work, we elucidate the inherent loss of net magnetization (⟨Iz⟩) in parahydrogen-induced polarization (PHIP) experiments with magnetic field cycling (MFC) for spin systems containing magnetically equivalent protons. The effects are shown for propane and diethyl ether as representative examples of potential hyperpolarized MRI contrast agents, but the findings of this work are equally applicable to other multispin systems in the liquid or gas phase. These results are relevant to both adiabatic longitudinal transport after dissociation engenders net alignment (ALTADENA) experiments (where 1H nuclei are polarized) and MFC protocols used to transfer parahydrogen spin order to a heteronucleus such as 13C.

Analysis of chemical exchange in iridium N-heterocyclic carbene complexes using heteronuclear parahydrogen-enhanced NMR.

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.

Rapid lung ventilation MRI using parahydrogen-induced polarization of propane gas.

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 (, anything besides protons, , C, N, Xe, Na, .). 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.

Developing Hyperpolarized Butane Gas for Ventilation Lung Imaging.

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 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.

Through-bond and through-space radiofrequency amplification by stimulated emission of radiation.

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.

Modeling Ligand Exchange Kinetics in Iridium Complexes Catalyzing SABRE Nuclear Spin Hyperpolarization.

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.

Branching-Chain Propagation of Parahydrogen-Derived Nuclear Spin Order on a Catalyst Surface.

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 molecules, which subsequently dissociate.

N Hyperpolarization of Metronidazole Antibiotic in Aqueous Media Using Phase-Separated Signal Amplification by Reversible Exchange with Parahydrogen.

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 [N]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three N sites achieved in less than 2 min.

Parahydrogen-Induced Polarization of N 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 N nuclei with natural isotopic abundance of >99 % is demonstrated.

Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent.

Hyperpolarized 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 Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton (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.

MATRESHCA: Microtesla Apparatus for Transfer of Resonance Enhancement of Spin Hyperpolarization via Chemical Exchange and Addition.

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 C and 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.

Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation of the Hyperpolarized Ketone and Hemiketal Forms of Allyl [1-C]Pyruvate.

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 C nuclear spins that also need to be synchronized with MRI field gradient pulses.

Ultra-Low-Cost Disposable Hand-Held Clinical-Scale Propane Gas Hyperpolarizer for Pulmonary Magnetic Resonance Imaging Sensing.

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.

Subsecond Three-Dimensional Nitrogen-15 Magnetic Resonance Imaging Facilitated by Parahydrogen-Based Hyperpolarization.

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.

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

Hyperpolarized (, 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 F and P) in a wide range of molecules.

Mechanisms of Methylenecyclobutane Hydrogenation over Supported Metal Catalysts Studied by Parahydrogen-Induced Polarization Technique.

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.

Parahydrogen-Induced Polarization Relayed via Proton Exchange.

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 (), fast reaction, and low cost with the broad applicability of polarization transfer via proton exchange.

Low-Cost High-Pressure Clinical-Scale 50% Parahydrogen Generator Using Liquid Nitrogen at 77 K.

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.

Heterogeneous Catalysis and Parahydrogen-Induced Polarization.

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.

Heterogeneous H and C Parahydrogen-Induced Polarization of Acetate and Pyruvate Esters.

Magnetic resonance imaging of [1- C]hyperpolarized carboxylates (most notably, [1- C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of H and 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- C-enriched forms with parahydrogen over Rh/TiO catalysts in methanol-d and in D O. The maximum obtained H polarization was 0.

Synthetic Approaches for N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields.

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 C and N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways.

Synthesis and N NMR Signal Amplification by Reversible Exchange of [ 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 N-labeled [ N]dalfampridine (4-amino[ 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.

Low-Flammable Parahydrogen-Polarized MRI Contrast Agents.

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.

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 [ N ]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next-generation MRI-LINAC systems.

Heterogeneous Parahydrogen-Induced Polarization of Diethyl Ether for Magnetic Resonance Imaging Applications.

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 Xe hyperpolarization for clinical MRI research is well developed, it requires the expensive equipment for production and detection of hyperpolarized Xe. Herein we present the H hyperpolarization of diethyl ether vapor that can be imaged on any clinical MRI scanner.