Parahydrogen-induced Polarization Research Articles

Constant-adiabaticity ultralow magnetic field manipulations of parahydrogen-induced polarization: application to an AA'X spin system.

The field of magnetic resonance imaging with hyperpolarized contrast agents is rapidly expanding, and parahydrogen-induced polarization (PHIP) is emerging as an inexpensive and easy-to-implement method for generating the required hyperpolarized biomolecules. Hydrogenative PHIP delivers hyperpolarized proton spin order to a substrate via chemical addition of H2 in the spin-singlet state, but it is typically necessary to transfer the proton polarization to a heteronucleus (usually 13C) which has a longer spin lifetime. Adiabatic ultralow magnetic field manipulations can be used to induce the polarization transfer, but this is necessarily a slow process, which is undesirable since the spins continually relax back to thermal equilibrium. Here we demonstrate two constant-adiabaticity field sweep methods, one in which the field passes through zero, and one in which the field is swept from zero, for optimal polarization transfer on a model AA'X spin system, [1-13C]fumarate. We introduce a method for calculating the constant-adiabaticity magnetic field sweeps, and demonstrate that they enable approximately one order of magnitude faster spin-order conversion compared to linear sweeps. The present method can thus be utilized to manipulate nonthermal order in heteronuclear spin systems.

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 2H-labeled molecules by exciting only the desired protons in a frequency-selective manner. This way, the effect of selected J-couplings is suspended. Experimentally 1.25% 13C polarization were obtained for 1-13C-ethyl pyruvate and 50% pH2 at 9.4 Tesla.

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.

Representation of population exchange at level anti-crossings.

A theoretical framework is proposed to describe the spin dynamics driven by coherent spin mixing at level anti-crossings (LACs). We briefly introduce the LAC concept and propose to describe the spin dynamics using a vector of populations of the diabatic eigenstates. In this description, each LAC gives rise to a pairwise redistribution of eigenstate populations, allowing one to construct the total evolution operator of the spin system. Additionally, we take into account that in the course of spin evolution a "rotation" of the eigenstate basis case take place. The approach is illustrated by a number of examples, dealing with magnetic field inversion, cross-polarization, singlet-state nuclear magnetic resonance and parahydrogen-induced polarization.

High-Pressure Clinical-Scale 87% Parahydrogen Generator.

We present an automated parahydrogen generator (ParaSun) for clinical-scale applications in parahydrogen-induced polarization (PHIP) and signal amplification by reversible exchange (SABRE) at high pressures. The device employs a vacuum-pumped, Sunpower cryo-cooler (typically employed for cooling cellular network antennas) to achieve up to ∼87% parahydrogen enrichment at a temperature as low as ∼40 K and a maximum outlet pressure of ∼490 PSI. The device reaches the target temperature set-point in under 1 h. It employs a FeO(OH) catalyst for the ortho- to para-state conversion. A mass-flow controller (MFC) facilitates the controlled flow of H2 gas at a rate of 150 standard cubic centimeters per minute (sccm). This design bridges the gap between rudimentary 50% enrichment liquid-N2 baths and far costlier, near-unity-enrichment configurations employing high-H2 throughputs and <25 K temperatures. The design presented here should be of interest for those pursuing a wide variety of PHIP applications, including those involving the production of inhalable or injectable hyperpolarized contrast agents for biomedical imaging.

SABRE and PHIP pumped RASER and the route to chaos

In a RASER (Radio-frequency Amplification by Stimulated Emission of Radiation), the fast relaxing electromagnetic modes of an LC resonator are enslaved by the slow nuclear spin motion, whose coherence decays with the transverse relaxation rate γm=1/T2∗. Such a system obeys the slaving principle, mathematically identical with the adiabatic elimination procedure, leading to multi-mode RASER equations. If the pumping rate of nuclear spin polarization Γ>>γm, a second adiabatic elimination process applies and the spectral properties of the RASER can be predicted. The resulting model is similar to the model of two non-linear coupled oscillators and predicts the observed RASER phenomena, including frequency combs and mode collapse. If the second adiabatic elimination is not applicable, mode collapse is completely absent and successive period doubling processes and chaos occur at very high population inversions. We compare these theoretical predictions with experimental results from a PHIP (Para-Hydrogen Induced Polarization) pumped 1H RASER. Moreover, in SABRE (Signal Amplification By Reversible Exchange) pumped 1H experiments, RASER revivals are observed long after the parahydrogen pumping source has been switched off. All these findings shed light onto the links between NMR spectroscopy, RASER physics, synergetics and chaos theory. Several new applications are envisioned in the fields of quantum sensor technology, structure investigation or magnetic resonance imaging (MRI).

Parahydrogen-Induced Hyperpolarization of Gases.

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.

Geminal parahydrogen-induced polarization: accumulating long-lived singlet order on methylene proton pairs.

In the majority of hydrogenative parahydrogen-induced polarization (PHIP) experiments, the hydrogen molecule undergoes pairwise cis addition to an unsaturated precursor to occupy vicinal positions on the product molecule. However, some ruthenium-based hydrogenation catalysts induce geminal hydrogenation, leading to a reaction product in which the two hydrogen atoms are transferred to the same carbon centre, forming a methylene () group. The singlet order of parahydrogen is substantially retained over the geminal hydrogenation reaction, giving rise to a singlet-hyperpolarized group. Although the relaxation times of the methylene protons are often short, the singlet order has a long lifetime, provided that singlet-triplet mixing is suppressed, either by chemical equivalence of the protons or by applying a resonant radiofrequency field. The long lifetime of the singlet order enables the accumulation of hyperpolarization during the slow hydrogenation reaction. We introduce a kinetic model for the behaviour of the observed hyperpolarized signals, including both the chemical kinetics and the spin dynamics of the reacting molecules. Our work demonstrates the feasibility of producing singlet-hyperpolarized methylene moieties by parahydrogen-induced polarization. This potentially extends the range of molecular agents which may be generated in a hyperpolarized state by chemical reactions of parahydrogen.

Progress in Creation of a New Constant Medium for Hyperpolarized MRI

The MRI (Magnetic Resonance Imaging) has been used as one of the powerful tools for medical diagnoses. Its usefulness is, however, still restricted because of the low spatial resolution and long measuring time mainly due to the low NMR (Nuclear Magnetic Resonance) signals relative to the noise levels. To overcome these restrictions, we started developing a method to remarkably enlarge the NMR signals about 10 years ago. We employ a method to hyperpolarize the nuclei, where the “hyperpolarize” means to artificially generate the nuclear polarization by many orders (102~106) of magnitude higher than the ordinary NMR signals currently in use. The hyperpolarized MRI would enable us to provide images with much higher spatial resolution and shorter measuring time than ever. Several techniques for hyperpolarization have been put into practical use; the BF (Brute Force) method, PHIP (Parahydrogen Induced Polarization) method, Laser optical pumping, DNP (Dynamic Nuclear Polarization), and so on. The experimental study on the hyperpolarization of 3He by the BF method, and that of 19F in PFC (Perfluorocarbon, known as an artificial blood) by the PHIP method has gotten started. In the former method, we use an extremely low temperature realized by the Pomeranchuk cooling in combination with 3He/4He dilution refrigerator and high magnetic field. In the latter method, we use the hydrogenation of the parahydrogen in the unsaturated hydrocarbon substrate at room temperature. Very recently, we started developing a novel type of the hyperpolarized MRI named HMM (Hyperpolarized Metabolic MRI) hoping for the cancer diagnosis.

In-vitro NMR Studies of Prostate Tumor Cell Metabolism by Means of Hyperpolarized [1-13C]Pyruvate Obtained Using the PHIP-SAH Method.

Nuclear Magnetic Resonance allows the non-invasive detection and quantitation of metabolites to be carried out in cells and tissues. This means that that metabolic changes can be revealed without the need for sample processing and the destruction of the biological matrix. The main limitation to the application of this method to biological studies is its intrinsic low sensitivity. The introduction of hyperpolarization techniques and, in particular, of dissolution-Dynamic Nuclear Polarization (d-DNP) and ParaHydrogen Induced Polarization (PHIP) is a significant breakthrough for the field as the MR signals of molecules and, most importantly, metabolites, can be increased by some orders of magnitude. Hyperpolarized pyruvate is the metabolite that has been most widely used for the investigation of metabolic alterations in cancer and other diseases. Although d-DNP is currently the gold-standard hyperpolarization method, its high costs and intrinsically slow hyperpolarization procedure are a hurdle to the application of this tool. However, PHIP is cost effective and fast and hyperpolarized pyruvate can be obtained using the so-called Side Arm Hydrogenation approach (PHIP-SAH). The potential toxicity of a solution of the hyperpolarized metabolite that is obtained in this way is presented herein. HP pyruvate has then been used for metabolic studies on different prostate cancer cells lines (DU145, PC3, and LnCap). The results obtained using the HP metabolite have been compared with those from conventional biochemical assays.

Continuous Radio Amplification by Stimulated Emission of Radiation using Parahydrogen Induced Polarization (PHIP-RASER) at 14 Tesla.

Nuclear Magnetic Resonance (NMR) is an intriguing quantum‐mechanical effect that is used for routine medical diagnostics and chemical analysis alike. Numerous advancements have contributed to the success of the technique, including hyperpolarized contrast agents that enable real‐time imaging of metabolism in vivo. Herein, we report the finding of an NMR radio amplification by stimulated emission of radiation (RASER), which continuously emits 1H NMR signal for more than 10 min. Using parahydrogen induced hyperpolarization (PHIP) with 50 % para‐hydrogen, we demonstrated the effect at 600 MHz but expect that it is functional across a wide range of frequencies, e.g. 101–103 MHz. PHIP‐RASER occurs spontaneously or can be triggered with a standard NMR excitation. Full chemical shift resolution was maintained, and a linewidth of 0.6 ppb was achieved. The effect was reproduced by simulations using a weakly coupled, two spin‐1/2 system. All devices used were standard issue, such that the effect can be reproduced by any NMR lab worldwide with access to liquid nitrogen for producing parahydrogen.

Spatially resolved NMR spectroscopy of heterogeneous gas phase hydrogenation of 1,3-butadiene with parahydrogen

Glass tube reactors with Pd, Pt, Rh or Ir nanoparticles dispersed on a thin layer of TiO2, CeO2, SiO2 or Al2O3 provided mechanistic insight into the hydrogenation of 1,3-butadiene using parahydrogen.

Biomedical Applications of the Dynamic Nuclear Polarization and Parahydrogen Induced Polarization Techniques for Hyperpolarized 13C MR Imaging.

Since the first pioneering report of hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI) of the Warburg effect in prostate cancer patients, clinical dissemination of the technique has been rapid; close to 10 sites worldwide now possess a polarizer fit for the clinic, and more than 30 clinical trials, predominantly for oncological applications, are already registered on the US and European clinical trials databases. Hyperpolarized 13C probes to study pathophysiological processes beyond the Warburg effect, including tricarboxylic acid cycle metabolism, intra-cellular pH and cellular necrosis have also been demonstrated in the preclinical arena and are pending clinical translation, and the simultaneous injection of multiple co-polarized agents is opening the door to high-sensitivity, multi-functional molecular MRI with a single dose. Here, we review the biomedical applications to date of the two polarization methods that have been used for in vivo hyperpolarized 13C molecular MRI; namely, dissolution dynamic nuclear polarization and parahydrogen-induced polarization. The basic concept of hyperpolarization and the fundamental theory underpinning these two key 13C hyperpolarization methods, along with recent technological advances that have facilitated biomedical realization, are also covered.

Pulse-Programmable Magnetic Field Sweeping of Parahydrogen-Induced Polarization by Side Arm Hydrogenation.

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 13C-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 13C 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 13C polarization of ethyl acetate-1-13C, i.e., the product of pairwise addition of parahydrogen to vinyl acetate-1-13C, 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 1H to 13C polarization transfer efficiency and (ii) the high reproducibility of the technique.

Real-Time Nuclear Magnetic Resonance Detection of Fumarase Activity Using Parahydrogen-Hyperpolarized [1-13C]Fumarate

Hyperpolarized fumarate can be used as a probe of real-time metabolism in vivo, using carbon-13 magnetic resonance imaging. Dissolution dynamic nuclear polarization is commonly used to produce hyperpolarized fumarate, but a cheaper and faster alternative is to produce hyperpolarized fumarate via PHIP (parahydrogen-induced polarization). In this work, we trans-hydrogenate [1-13C]acetylene dicarboxylate with para-enriched hydrogen using a commercially available Ru catalyst in water to produce hyperpolarized [1-13C]fumarate. We show that fumarate is produced in 89% yield, with succinate as a side product in 11% yield. The proton polarization is converted into 13C magnetization using a constant adiabaticity field cycle, and a polarization level of 24% is achieved using 86% para-enriched hydrogen gas. We inject the hyperpolarized [1-13C]fumarate into cell suspensions and track the metabolism. This work opens the path to greatly accelerated preclinical studies using fumarate as a biomarker.

Parahydrogen-induced polarization in the hydrogenation of lignin-derived phenols using Wilkinson’s catalyst

We herein report our new hydrogenation strategy realized at room temperature and atmospheric pressure for stabilizing lignin model phenols in the presence of Wilkinson’s catalyst (RhCl(PPh3)3). To the best of our knowledge, we first employed a parahydrogen for the hydrogenation study of lignin-derived reactive phenols with vinyl- and allyl groups, and parahydrogen-induced polarization was observed in-situ using a benchtop NMR spectroscopic system. The results clearly showed the saturation of those reactive functional groups with Wilkinson’s catalyst as well as enhanced spin polarizations, which will be a firm basis for developing new types of hydrogenation catalysts in mild conditions. The benchtop NMR system integrated with the use of parahydrogen and homogeneous hydrogenation processes employed in this study could provide insights toward new fundamental applications. Furthermore, this strategy shows potential for developing a new practical analytical tool with highly polarized nuclear spins in the lignin-based biorefineries.

A Simple and Efficient Procedure for Rh(I)‐ and Ir(I)‐complex Catalyzed Para‐hydrogenation of Alkynes and Alkenes in Aqueous Media Resulting in Strong PHIP Effects

AbstractCatalytic hydrogenations with para‐H2 may lead to strong para‐hydrogen induced polarization (PHIP) and the hyperpolarized probe molecules may enable the application of the Magnetic Resonance Imaging (MRI) diagnostic modality for metabolism imaging. The use of water as a solvent for para‐hydrogenation reactions is very challenging due to the fast exchange between the catalytically active metal hydrides and the water protons and also because of the low hydrogen solubility in water. Here we report that several water‐soluble Rh(I)‐ and Ir(I)‐complexes with N‐heterocyclic carbene (NHC) and/or tertiary phosphine ligands efficiently catalyze the synthesis of hyperpolarized compounds by para‐hydrogenation in aqueous media.

Parahydrogen-Induced Polarization of 1-13C-Acetates and 1-13C-Pyruvates Using Sidearm Hydrogenation of Vinyl, Allyl, and Propargyl Esters.

13C-hyperpolarized carboxylates, such as pyruvate and acetate, are emerging molecular contrast agents for MRI visualization of various diseases, including cancer. Here we present a systematic study of 1H and 13C parahydrogen-induced polarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties. It was found that allyl pyruvate is the most efficiently hyperpolarized compound from those under study, yielding 21% and 5.4% polarization of 1H and 13C nuclei, respectively, in CD3OD solutions. Allyl pyruvate and ethyl acetate were also hyperpolarized in aqueous phase using homogeneous hydrogenation with parahydrogen over water-soluble rhodium catalyst. 13C polarization of 0.82% and 2.1% was obtained for allyl pyruvate and ethyl acetate, respectively. 13C-hyperpolarized methanolic and aqueous solutions of allyl pyruvate and ethyl acetate were employed for in vitro MRI visualization, demonstrating the prospects for translation of the presented approach to biomedical in vivo studies.

Clinical-Scale Batch-Mode Production of Hyperpolarized Propane Gas for MRI.

NMR spectroscopy and imaging (MRI) are two of the most important methods to study structure, function, and dynamics from atom to organism scale. NMR approaches often suffer from an insufficient sensitivity, which, however, can be transiently boosted using hyperpolarization techniques. One of these techniques is parahydrogen-induced polarization, which has been used to produce catalyst-free hyperpolarized propane gas with proton polarization that is 3 orders of magnitude greater than equilibrium thermal polarization at a 1.5 T field of a clinical MRI scanner. Here we show that more than 0.3 L of hyperpolarized propane gas can be produced in 2 s. This production rate is more than an order of magnitude greater than that demonstrated previously, and the reported production rate is comparable to that employed for in-human MRI using HP noble gas (e.g., 129Xe) produced via a spin exchange optical pumping (SEOP) hyperpolarization technique. We show that high polarization values can be retained despite the significant increase in the production rate of hyperpolarized propane. The enhanced signals of produced hyperpolarized propane gas were revealed by stopped-flow MRI visualization at 4.7 T. Achieving this high production rate enables the future use of this compound (already approved for unlimited use in foods by the corresponding regulating agencies, e.g., FDA in the USA, and more broadly as an E944 food additive) as a new inhalable contrast agent for diagnostic detection via MRI.

Ultrafast Single-Scan 2D NMR Spectroscopic Detection of a PHIP-Hyperpolarized Protease Inhibitor.

Two-dimensional NMR spectroscopy is one of the most important spectroscopic tools for the investigation of biological macromolecules. However, due to the low sensitivity of NMR spectroscopy, it takes usually from several minutes to many hours to record such spectra. Here, the possibility of detecting a bioactive derivative of the sunflower trypsin inhibitor-1 (SFTI-1), a tetradecapeptide, by combining parahydrogen-induced polarization (PHIP) and ultrafast 2D NMR spectroscopy is shown. The PHIP activity of the inhibitor was achieved by labeling with O-propargyl-l-tyrosine. In 1D PHIP experiments a signal enhancement of a factor of approximately 1200 compared to standard NMR was found. This enhancement permits measurement of 2D NMR correlation spectra of low-concentrated SFTI-1 in less than 10 seconds, employing ultrafast single-scan 2D NMR detection. As experimental examples PHIP-assisted ultrafast single-scan TOCSY spectra of SFTI-1 are shown.