RASER for Increased Spectral Resolution in Carbon-13 NMR.

Precision in nuclear magnetic resonance (NMR) spectroscopy and resolution in magnetic resonance imaging (MRI) are thought to be fundamentally limited by the transverse relaxation time. With the recent advent of radiofrequency amplification by stimulated emission of radiation (RASER), it is becoming apparent that RASERs can break these fundamental limitations and provide significant improvements in the resolution of NMR spectra and the resolution in MRI images. In this article, we show that carbon-13 RASERs can be controlled by changes to the magnetic field homogeneity and the spin coupling network.

Continuous Delivery of Hyperpolarized Xenon-129 Gas Using a "Stopped-Flow" Clinical-Scale Cryogen-Free Hyperpolarizer.

In 2022, the FDA approved hyperpolarized (HP) Xe gas as an inhalable contrast agent for functional lung imaging. For clinical imaging, HP Xe is usually given as a bolus inhalation. However, for preclinical applications (e.

N SABRE-SHEATH and NMR/DFT Characterization of Amino-Metronidazole, a Metabolic Product of the Antibiotic and Prospective Hypoxia Contrast Agent Metronidazole.

The antibiotic metronidazole (MNZ) has gained interest as a potential MRI contrast agent for imaging hypoxia. N-labeled MNZ can be efficiently hyperpolarized via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei), but the envisioned MRI approach requires that MNZ rapidly undergoes structural changes in hypoxic environments with significant N frequency differences manifested in its downstream metabolic products. We have performed NMR studies of the anticipated metabolic product amino-MNZ (despite anticipated stability concerns) accompanied by computational density functional theory (DFT) studies to predict the N chemical shifts of different relevant species.

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.

SABRE-SHEATH Hyperpolarization of [1,5-C]Z-OMPD for Noninvasive pH Sensing.

Hyperpolarized (HP) C-labeled probes are emerging as promising agents to noninvasively image pH in vivo. HP [1,5-C]Z-OMPD (Z-4-methyl-2-oxopent-3-enedioic acid) in particular has recently been used to simultaneously report on kidney perfusion, filtration, and pH homeostasis, in addition to the ability to detect local tumor acidification. In previous studies, dissolution dynamic nuclear polarization was used to hyperpolarize Z-OMPD.

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.

Rapid in situ carbon-13 hyperpolarization and imaging of acetate and pyruvate esters without external polarizer.

Hyperpolarized C MRI visualizes real-time metabolic processes in vivo. In this study, we achieved high C polarization in situ in the bore of an MRI system for precursor molecules of most widely employed hyperpolarized agents: [1-C]acetate and [1-C]pyruvate ethyl esters in their perdeuterated forms, enhancing hyperpolarization lifetimes, hyperpolarized to P ≈ 28% at 80 mM concentration and P ≈ 19% at 10 mM concentration, respectively. Using vinyl esters as unsaturated Parahydrogen-Induced Polarization via Side-Arm Hydrogenation (PHIP-SAH) precursors and our novel polarization setup, we achieved these hyperpolarization levels by fast side-arm hydrogenation in acetone-d at elevated temperatures (up to 90°C) and hydrogenation pressures (up to 32 bar).

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.

Low-Cost Purpose-Built Ultra-Low-Field NMR Spectrometer.

Low-field NMR has emerged as a new analytical technique for the investigation of molecular structure and dynamics. Here, we introduce a highly integrated ultralow-frequency NMR spectrometer designed for the purpose of ultralow-field NMR polarimetry of hyperpolarized contrast media. The device measures 10 cm × 10 cm × 2.

Carbon-13 Hyperpolarization of α-Ketocarboxylates with Parahydrogen in Reversible Exchange.

Signal Amplification by Reversible Exchange (SABRE) is a relatively simple and fast hyperpolarization technique that has been used to hyperpolarize the α-ketocarboxylate pyruvate, a central metabolite and the leading hyperpolarized MRI contrast agent. In this work, we show that SABRE can readily be extended to hyperpolarize C nuclei at natural abundance on many other α-ketocarboxylates. Hyperpolarization is observed and optimized on pyruvate (P=17 %) and 2-oxobutyrate (P=25 %) with alkyl chains in the R-group, oxaloacetate (P=11 %) and alpha-ketoglutarate (P=13 %) with carboxylate moieties in the R group, and phenylpyruvate (P=2 %) and phenylglyoxylate (P=2 %) with phenyl rings in the R-group.

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.

Toward Next-Generation Molecular Imaging with a Clinical Low-Field (0.064 T) Point-of-Care MRI Scanner.

Low-field (LF) MRI promises soft-tissue imaging without the expensive, immobile magnets of clinical scanners but generally suffers from limited detection sensitivity and contrast. The sensitivity boost provided by hyperpolarization can thus be highly synergistic with LF MRI. Initial efforts to integrate a continuous-bubbling SABRE (signal amplification by reversible exchange) hyperpolarization setup with a portable, point-of-care 64 mT clinical MRI scanner are reported.

In vivo Metabolic Sensing of Hyperpolarized [1-C]Pyruvate in Mice Using a Recyclable Perfluorinated Iridium Signal Amplification by Reversible Exchange Catalyst.

Real-time visualization of metabolic processes in vivo provides crucial insights into conditions like cancer and metabolic disorders. Metabolic magnetic resonance imaging (MRI), by amplifying the signal of pyruvate molecules through hyperpolarization, enables non-invasive monitoring of metabolic fluxes, aiding in understanding disease progression and treatment response. Signal Amplification By Reversible Exchange (SABRE) presents a simpler, cost-effective alternative to dissolution dynamic nuclear polarization, eliminating the need for expensive equipment and complex procedures.

Toward Ultra-High-Quality-Factor Wireless Masing Magnetic Resonance Sensing.

It has recently been shown that a bolus of hyperpolarized nuclear spins can yield stimulated emission signals similar in nature to maser signals, potentially enabling new ways of sensing hyperpolarized contrast media, including most notably [1-C]pyruvate that is under evaluation in over 50 clinical trials for metabolic imaging of cancer. The stimulated NMR signal emissions lasting for minutes do not require radio-frequency excitation, offering unprecedented advantages compared to conventional MR sensing. However, creating nuclear spin maser emission is challenging in practice due to stringent fundamental requirements, making practical in vivo applications hardly possible using conventional passive MR detectors.

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.

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.

Perfluorinated Iridium Catalyst for Signal Amplification by Reversible Exchange Provides Metal-Free Aqueous Hyperpolarized [1-C]-Pyruvate.

Hyperpolarized (HP) carbon-13 [C] enables the specific investigation of dynamic metabolic and physiologic processes via in vivo MRI-based molecular imaging. As the leading HP metabolic agent, [1-C]pyruvate plays a pivotal role due to its rapid tissue uptake and central role in cellular energetics. Dissolution dynamic nuclear polarization (d-DNP) is considered the gold standard method for the production of HP metabolic probes; however, development of a faster, less expensive technique could accelerate the translation of metabolic imaging via HP MRI to routine clinical use.

Facile hyperpolarization chemistry for molecular imaging and metabolic tracking of [1-C]pyruvate in vivo.

Hyperpolarization chemistry based on reversible exchange of parahydrogen, also known as Signal Amplification By Reversible Exchange (SABRE), is a particularly simple approach to attain high levels of nuclear spin hyperpolarization, which can enhance NMR and MRI signals by many orders of magnitude. SABRE has received significant attention in the scientific community since its inception because of its relative experimental simplicity and its broad applicability to a wide range of molecules, however in vivo detection of molecular probes hyperpolarized by SABRE has remained elusive. Here we describe a first demonstration of SABRE-hyperpolarized contrast detected in vivo, specifically using hyperpolarized [1-C]pyruvate.

Delivering Robust Proton-Only Sensing of Hyperpolarized [1,2-C]-Pyruvate Using Broad-Spectral-Range Nuclear Magnetic Resonance Pulse Sequences.

Hyperpolarized [1-C]pyruvate is the leading hyperpolarized injectable contrast agent and is currently under evaluation in clinical trials for molecular imaging of metabolic diseases, including cardiovascular disease and cancer. One aspect limiting broad scalability of the technique is that hyperpolarized C MRI requires specialized C hardware and software that are not generally available on clinical MRI scanners, which employ proton-only detection. Here, we present an approach that uses pulse sequences to transfer C hyperpolarization to methyl protons for detection of the C-C pyruvate singlet, employing proton-only excitation and detection only.

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.

Dramatic improvement in the "Bulk" hyperpolarization of Xe via spin exchange optical pumping probed using in situ low-field NMR.

We report on hyperpolarization of quadrupolar (I=3/2) Xe via spin-exchange optical pumping. Observations of the Xe polarization dynamics via in situ low-field NMR show that the estimated alkali-metal/Xe spin-exchange rates can be large enough to compete with Xe spin relaxation. Xe polarization up to 7.