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 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.

Yeast Solutions and Hyperpolarization Enable Real-Time Observation of Metabolized Substrates Even at Natural Abundance.

Metabolic changes in an organism often occur much earlier than macroscopic manifestations of disease, such as invasive tumors. Therefore, noninvasive tools to monitor metabolism are fundamental as they provide insights into in vivo biochemistry. NMR represents one of the gold standards for such insights by observing metabolites.

Nuclear spin polarization of lactic acid via exchange of parahydrogen-polarized protons.

Hyperpolarization has become a powerful tool to enhance the sensitivity of magnetic resonance. A universal tool to hyperpolarize small molecules in solution, however, has not yet emerged. Transferring hyperpolarized, labile protons between molecules is a promising approach towards this end.

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.

C MRI of hyperpolarized pyruvate at 120 µT.

Nuclear spin hyperpolarization increases the sensitivity of magnetic resonance dramatically, enabling many new applications, including real-time metabolic imaging. Parahydrogen-based signal amplification by reversible exchange (SABRE) was employed to hyperpolarize [1-C]pyruvate and demonstrate C imaging in situ at 120 µT, about twice Earth's magnetic field, with two different signal amplification by reversible exchange variants: SABRE in shield enables alignment transfer to heteronuclei (SABRE-SHEATH), where hyperpolarization is transferred from parahydrogen to [1-C]pyruvate at a magnetic field below 1 µT, and low-irradiation generates high tesla (LIGHT-SABRE), where hyperpolarization was prepared at 120 µT, avoiding magnetic field cycling. The 3-dimensional images of a phantom were obtained using a superconducting quantum interference device (SQUID) based magnetic field detector with submillimeter resolution.

Coupling Constants of <1 Hz Enable C Hyperpolarization of Pyruvate via Reversible Exchange of Parahydrogen.

Observing pyruvate metabolism has become a focal point of molecular magnetic resonance imaging. Signal amplification by reversible exchange (SABRE) has recently emerged as a versatile hyperpolarization technique. Tuning of the spin order transfer (SOT) in SABRE is challenging as the small H-C couplings, in the C-pyruvate case, result in SOT being not readily discernible.

Exceptionally Mild and High-Yielding Synthesis of Vinyl Esters of Alpha-Ketocarboxylic Acids, Including Vinyl Pyruvate, for Parahydrogen-Enhanced Metabolic Spectroscopy and Imaging.

Metabolic changes often occur long before pathologies manifest and treatment becomes challenging. As key elements of energy metabolism, α-ketocarboxylic acids (α-KCA) are particularly interesting, e.g.

Nitrogen-15 dynamic nuclear polarization of nicotinamide derivatives in biocompatible solutions.

Dissolution dynamic nuclear polarization (dDNP) increases the sensitivity of magnetic resonance imaging by more than 10,000 times, enabling in vivo metabolic imaging to be performed noninvasively in real time. Here, we are developing a group of dDNP polarized tracers based on nicotinamide (NAM). We synthesized 1-N-NAM and 1-N nicotinic acid and hyperpolarized them with dDNP, reaching (13.

Spying on parahydrogen-induced polarization transfer using a half-tesla benchtop MRI and hyperpolarized imaging enabled by automation.

Nuclear spin hyperpolarization is a quantum effect that enhances the nuclear magnetic resonance signal by several orders of magnitude and has enabled real-time metabolic imaging in humans. However, the translation of hyperpolarization technology into routine use in laboratories and medical centers is hampered by the lack of portable, cost-effective polarizers that are not commercially available. Here, we present a portable, automated polarizer based on parahydrogen-induced hyperpolarization (PHIP) at an intermediate magnetic field of 0.

LIGHT-SABRE Hyperpolarizes 1-C-Pyruvate Continuously without Magnetic Field Cycling.

Nuclear spin hyperpolarization enables real-time observation of metabolism and intermolecular interactions . 1-C-pyruvate is the leading hyperpolarized tracer currently under evaluation in several clinical trials as a promising molecular imaging agent. Still, the quest for a simple, fast, and efficient hyperpolarization technique is ongoing.

Modern Manufacturing Enables Magnetic Field Cycling Experiments and Parahydrogen-Induced Hyperpolarization with a Benchtop NMR.

Benchtop NMR (btNMR) spectrometers are revolutionizing the way we use NMR and lowering the cost drastically. Magnetic field cycling (MFC) experiments with precise timing and control over the magnetic field, however, were hitherto not available on btNMRs, although some systems exist for high-field, high-resolution NMR spectrometers. Still, the need and potential for btNMR MFC is great─e.

Parahydrogen-induced polarization and spin order transfer in ethyl pyruvate at high magnetic fields.

Nuclear magnetic resonance has experienced great advances in developing and translating hyperpolarization methods into procedures for fundamental and clinical studies. Here, we propose the use of a wide-bore NMR for large-scale (volume- and concentration-wise) production of hyperpolarized media using parahydrogen-induced polarization. We discuss the benefits of radio frequency-induced parahydrogen spin order transfer, we show that 100% polarization is theoretically expected for homogeneous B and B magnetic fields for a three-spin system.

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.

[Hyperpolarized C magnetic resonance imaging-a window into metabolism : High-resolution images of human metabolism].

Clinical Issue: Despite being one of the main pillars of modern diagnostics, magnetic resonance imaging (MRI) uses only a tiny fraction of its potential: no more than a millionth of all nuclear spins contribute to the MRI signal. In order to increase this fraction, called polarization, MRI scanners with stronger magnetic fields are being developed. However, even the most modern scanners do not exploit the potential of MRI.

Synthesis of C and H Labeled Vinyl Pyruvate and Hyperpolarization of Pyruvate.

The hyperpolarization of nuclear spins has enabled unique applications in chemistry, biophysics, and particularly metabolic imaging. Parahydrogen-induced polarization (PHIP) offers a fast and cost-efficient way of hyperpolarization. Nevertheless, PHIP lags behind dynamic nuclear polarization (DNP), which is already being evaluated in clinical studies.

Frequency-Selective Manipulations of Spins allow Effective and Robust Transfer of Spin Order from Parahydrogen to Heteronuclei in Weakly-Coupled Spin Systems.

We present a selectively pulsed (SP) generation of sequences to transfer the spin order of parahydrogen (pH ) to heteronuclei in weakly coupled spin systems. We analyze and discuss the mechanism and efficiency of SP spin order transfer (SOT) and derive sequence parameters. These new sequences are most promising for the hyperpolarization of molecules at high magnetic fields.

Selective excitation of hydrogen doubles the yield and improves the robustness of parahydrogen-induced polarization of low-γ nuclei.

We describe a new method for pulsed spin order transfer of parahydrogen-induced polarization (PHIP) that enables high polarization in incompletely H-labeled molecules by exciting only the desired protons in a frequency-selective manner. This way, the effect of selected -couplings is suspended. Experimentally 1.

Coherent Evolution of Signal Amplification by Reversible Exchange in Two Alternating Fields (alt-SABRE).

Parahydrogen (pH ) is a convenient and cost-efficient source of spin order to enhance the magnetic resonance signal. Previous work showed that transient interaction of pH with a metal organic complex in a signal amplification by reversible exchange (SABRE) experiment enabled more than 10 % polarization for some N molecules. Here, we analyzed a variant of SABRE, consisting of a magnetic field alternating between a low field of ∼1 μT, where polarization transfer is expected to take place, and a higher field >50 μT (alt-SABRE).

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.

Selective excitation doubles the transfer of parahydrogen-induced polarization to heteronuclei.

In this work, we present a new pulse sequence to transform the spin order added to a molecule after the pairwise addition of parahydrogen into 13C polarization. Using a selective 90° preparation instead of a non-selective 45° excitation, the new variant performed twice as well as previous implementations in both simulations and experiments, exemplified with hyperpolarized ethyl acetate. This concept is expected to extend to other nuclei and other spin order transfer schemes that use non-selective excitation.