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We introduce a Spin Transfer Automated Reactor (STAR) that produces continuous parahydrogen induced polarization (PHIP), which is stable for hours to days. We use the PHIP variant called signal amplification by reversible exchange (SABRE), which is particularly well suited to produce continuous hyperpolarization. The STAR is operated in conjunction with benchtop (1.1 T), and high field (9.4 T) NMR magnets, highlighting the versatility of this system to operate with any NMR or MRI system. The STAR uses semipermeable membranes to efficiently deliver parahydrogen into solutions at nano to milli Tesla fields, which enables (1)H, (13)C and (15)N hyperpolarization on a large range of substrates including drugs and metabolites. The unique features of the STAR are leveraged for important applications, including continuous hyperpolarization of metabolites, desirable for examining steady-state metabolism in vivo as well as for continuous RASER signals desirable for the investigation of new physics.

We report on the utility of Radiofrequency Amplification by Stimulated Emission Radiation (RASER) for background-free proton detection of hyperpolarized biomolecules. We performed hyperpolarization of ≈0.3 M ethyl acetate via pairwise parahydrogen addition to vinyl acetate. A proton NMR signal with signal-to-noise ratio exceeding 100 000 was detected without radio-frequency excitation at the clinically relevant magnetic field of 1.4 T using a standard (non-cryogenic) inductive detector with quality factor of Q=68. No proton background signal was observed from protonated solvent (methanol) or other added co-solvents such as ethanol, water or bovine serum. Moreover, we demonstrate RASER detection without radio-frequency excitation of a bolus of hyperpolarized contrast agent in biological fluid. Completely background-free proton detection of hyperpolarized contrast agents in biological media paves the way to new applications in the areas of high-resolution NMR spectroscopy and in vivo spectroscopy and imaging.

Signal amplification by reversible exchange (SABRE) is a robust and inexpensive hyperpolarization (HP) technique to enhance nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI) signals using parahydrogen (pH(2)). The substrate scope of SABRE is continually expanding. Here, we present the polarization of three antifungal drugs (voriconazole, clotrimazole and fluconazole) and elicit the detailed HP mechanisms for (1)H and (15)N nuclei. In this exploratory work, (15)N polarization values of ~1% were achieved using 50% pH(2) in solution of 3 mM catalyst and 60 mM substrate in perdeuterated methanol. All hyperpolarized (15)N sites exhibited long T(1) in excess of 1 minute at a clinically relevant field of 1 T. Hyperpolarizing common drugs is of interest due to their potential biomedical applications as MRI contrast agents or to enable studies on protein dynamics at physiological concentrations. We optimize the polarization with respect to temperature and the polarization transfer field (PTF) for (1)H nuclei in the millitesla regime and for (15)N nuclei in the microtesla regime, which provides detailed insights into exchange kinetics and spin evolution. This work broadens the SABRE substrate scope and provides mechanistic and kinetic insights into the HP process.

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.

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 increases 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.

The unique properties of the entangled, antisymmetric nuclear spin state of dihydrogen, parahydrogen (pH2), has intrigued physicists, chemists, and other scientists for almost a century. pH2 was used as a model system in the early days of quantum mechanics (1) and is used for fueling rockets as well as combustion-free cars today. In the 1980s, pH2 was discovered as a convenient and potent source of spin order, allowing the enhancement of the signals of magnetic resonance (MR) by several orders of magnitude. (2−4) In the advent of hyperpolarized (HP) contrast agents (CA) for biomedical MR imaging (MRI) that followed, pH2-based hyperpolarization methods played an important role in the acquisition of the first HP 13C in vivo images (Figure 1). (5,6) Ever since, pH2 has proven to be highly valuable for analytical investigations and fundamental research, e.g., in analytical and catalytic chemistry or in the physics of singlet spin states. (7−10).

Signal Amplification By Reversible Exchange in SHield Enabled Alignment Transfer (SABRE-SHEATH) is investigated to achieve rapid hyperpolarization of (13)C(1) spins of [1-(13)C]pyruvate, using parahydrogen as the source of nuclear spin order. Pyruvate exchange with an iridium polarization transfer complex can be modulated via a sensitive interplay between temperature and co-ligation of DMSO and H(2)O. Order-unity (13)C (>50%) polarization of catalyst-bound [1-(13)C]pyruvate is achieved in less than 30 s by restricting the chemical exchange of [1-(13)C]pyruvate at lower temperatures. On the catalyst bound pyruvate, 39% polarization are measured using 1.4 T NMR spectrometer, and extrapolated to >50% at the end of build-up in situ. The highest measured polarization of a 30-mM pyruvate sample, including free and bound pyruvate is 13% when using 20 mM DMSO and 0.5 M water in CD(3)OD. Efficient (13)C polarization is also enabled by favorable relaxation dynamics in sub-microtesla magnetic fields, as indicated by fast polarization buildup rates compared to the T(1) spin-relaxation rates (e.g., ~0.2 s(−1) versus ~0.1 s(−1), respectively, for a 6 mM catalyst-[1-(13)C]pyruvate sample). Finally, the catalyst-bound hyperpolarized [1-(13)C]pyruvate can be released rapidly by cycling the temperature and/or by optimizing the amount of water, paving the way to future biomedical applications of hyperpolarized [1-(13)C]pyruvate produced via comparatively fast and simple SABRE-SHEATH-based approaches.

Signal Amplification By Reversible Exchange (SABRE) is a particularly simple hyperpolarisation approach. However, compared to other hyperpolarisation methods, SABRE is more limited in substrate scope. Therefore, it is critical to understand and overcome the factors limiting generalization. Past developments in SABRE catalyst optimization have emphasized large enhancements in the canonical SABRE substrate: pyridine and structurally closely related motifs. However, the pyridine-optimized catalysts are not efficient at hyperpolarising more sterically demanding substrates, including 2-substituted pyridine derivatives. Here we report that modifications of the catalyst ligand sphere, using a chelating ligand in particular, can increase the volume fraction available for substrate coordination to the iridium catalyst, thus permitting significant signal enhancements on otherwise sterically hindered substrates. The system yields (1)H enhancements on the order of 100-fold over 8.5 T thermal measurements for 2-substituted pyridine derivatives, and smaller, yet significant (1)H enhancement for provitamin B(6) and caffeine. For the 2-substituted pyridine derivatives we further show (15)N enhancements on the order of 1000-fold and (19)F enhancements of 30-fold over 8.5 T thermal polarisations.

Magnetic Resonance Imaging (MRI) is a powerful non-invasive diagnostic method extensively used in biomedical studies. A significant limitation of MRI is its relatively low signal-to-noise ratio, which can be increased by hyperpolarizing nuclear spins. One promising method is Signal Amplification By Reversible Exchange (SABRE), which employs parahydrogen as a source of hyperpolarization. Recent studies demonstrated the feasibility to improve MRI sensitivity with this hyperpolarization technique. Hyperpolarized (15)N nuclei in biomolecules can potentially retain their spin alignment for tens of minutes, providing an extended time window for the utilization of the hyperpolarized compounds. In this work, we demonstrate for the first time that radio-frequency-based SABRE hyperpolarization techniques can be used to obtain (15)N MRI of biomolecule 1-(15)N-nicotinamide. Two image acquisition strategies were utilized and compared: Single Point Imaging (SPI) and Fast Low Angle SHot (FLASH). These methods demonstrated opportunities of high-field SABRE for biomedical applications.

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 three 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 liters of hyperpolarized propane gas can be produced in 2 seconds. 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 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 already compound (already approved for unlimited use in foods by the corresponding regulating agencies, e.g. FDA in the USA, and more broadly as E944 food additive) as a new inhalable contrast agent for diagnostic detection via MRI.

Current metabolic imaging in humans is dominated by positron emission tomography (PET) methods. An emerging non-ionizing alternative for molecular imaging is hyperpolarized MRI. In particular, imaging of hyperpolarized 13C-pyruvate is a leading candidate because pyruvate is innocuous and has a central role in metabolism. However, simi-lar to PET, hyperpolarized MRI with dynamic nuclear polarization (DNP) is complex, costly and requires complex in-frastructure. In contrast, signal amplification by reversible exchange (SABRE) is a fast, cheap, and scalable hyperpo-larization technique. In particular, SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) transfers polarization from parahydrogen to 13C in pyruvate, however, to date, SABRE-SHEATH of 13C-pyruvate was limited in polarization levels relative to DNP (1.7% with SABRE-SHEATH vs. ~60% with DNP). Here we introduce a temperature cycling method for SABRE-SHEATH that enables >10% polarization on [1-13C]pyruvate, sufficient for successful in vivo experiments. First, at lower temperatures, ~20% polarization is accumulated on SABRE-catalyst bound pyruvate, which is subsequently released into free pyruvate in solution at elevated temperatures. We take ad-vantage of the achieved polarization to demonstrate first 13C pyruvate images with a cryogen-free MRI system operat-ed at 1 T. This illustrates that inexpensive hyperpolarization methods can be combined with low-cost MRI systems to obtain a broadly available, yet highly sensitive metabolic imaging platform.

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 [1-13C]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 13C signal enhancement of over 14,000-fold at a clinically relevant magnetic field of 1 T corresponding to approximately 1.2% 13C polarization-if near 100% parahydrogen would have been employed, the reported value would be tripled to 13C polarization of 3.5%.

[Image: see text] We report on the inexpensive ($80) custom electronics for efficient robust and fast degaussing of mu-metal shields for use in parahydrogen induced polarization experiments. The degaussing process is fully automated and can be performed in ~2 seconds resulting in residual magnetic field of

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. Here 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.

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.

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This massive sensitivity gain enables new applications ranging from studies of small molecules 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 (13)C- and (15)N- sites of biocompatible agents are the key targets due to their widespread in biochemical pathways. Moreover, their long T(1) allows retaining hyperpolarized states 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 hyperpolarization of (15)N nuclei. While large sensitivity gains are enabled by hyperpolarization, (15)N natural abundance is only ~0.4%, so that isotopic labeling of the to-be-hyperpolarized molecules is required in order to take full advantage of the hyperpolarized state. Here, we describe selected advances in the preparation of (15)N-labeled compounds with the primary emphasis on using these compounds for their SABRE polarization in microtesla magnetic fields via 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.

The signal enhancement provided by the hyperpolarization of nuclear spins of metabolites is a promising technique for diagnostic magnetic resonance imaging (MRI). To date, most (13)C-contrast agents are hyperpolarized utilizing a complex or cost-intensive polarizer. Recently, the in situ parahydrogen-induced (13)C hyperpolarization was demonstrated. Hydrogenation, spin order transfer (SOT) by a pulsed NMR sequence, in vivo administration, and detection was achieved within the magnet bore of a 7 Tesla MRI system. So far, the hyperpolarization of the xenobiotic molecule 1-(13)C-hydroxyethylpropionate (HEP) and the biomolecule 1-(13)C-succinate (SUC) through the PH-INEPT+ sequence and a SOT scheme proposed by Goldman et al., respectively, was shown. Here, we investigate further the hyperpolarization of SUC at 7 Tesla and study the performance of two additional SOT sequences. Moreover, we present first results of the hyperpolarization at high magnetic field of 1-(13)C-phospholactate (PLAC), a derivate to obtain the metabolite lactate, employing the PH-INEPT+ sequence. For SUC and PLAC, (13)C polarizations of about 1–2 % were achieved within seconds and with minimal equipment. Effects that potentially may explain loss of (13)C polarization have been identified, i.e. low hydrogenation yield, fast T(1)/T(2) relaxation and the rarely considered (13)C isotope labeling effect.

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

(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 polarization transfer catalyst and quadrupolar (14)N nucleus within the spin-relayed (15)N-(15)N network.

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 non-toxic, 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 3-fold, paving the way to bioimaging applications and beyond.

Signal amplification by reversible exchange (SABRE) is an efficient method to hyperpolarize spin-1/2 nuclei and affords signals that are orders of magnitude larger than those obtained by thermal spin polarization. Direct polarization transfer to heteronuclei such as 13C or 15N has been optimized at static microTesla fields or using coherence transfer at high field, and relies on steady state exchange with the polarization transfer catalyst dictated by chemical kinetics. Here we demonstrate that pulsing the excitation field induces complex coherent polarization transfer dynamics, but in fact pulsing with a roughly 1% duty cycle on resonance produces more magnetization than constantly being on resonance. We develop a Monte Carlo simulation approach to unravel the coherent polarization dynamics, show that existing SABRE approaches are quite inefficient in use of para-hydrogen order, and present improved sequences for efficient hyperpolarization., There is increasing effort to improve the signal sensitivity and explore the hyperpolarization dynamics. Here the authors demonstrate the parahydrogen spin transfer dynamics in compounds containing 15N using SABRE hyperpolarization technique with different strengths of the magnetic field.

PURPOSE: Phospholipids are key constituents of cell membranes and serve vital functions in the regulation of cellular processes; thus, a method for in vivo detection and characterization could be valuable for detecting changes in cell membranes that are consequences of either normal or pathological processes. Here, we describe a new method to map the distribution of partially restricted phospholipids in tissues. METHODS: The phospholipids were measured by signal changes caused by relayed nuclear Overhauser enhancement-mediated CEST between the phospholipid Cho headgroup methyl protons and water at around −1.6 ppm from the water resonance. The biophysical basis of this effect was examined by controlled manipulation of head group, chain length, temperature, degree of saturation, and presence of cholesterol. Additional experiments were performed on animal tumor models to evaluate potential applications of this novel signal while correcting for confounding contributions. RESULTS: Negative relayed nuclear Overhauser dips in Z-spectra were measured from reconstituted Cho phospholipids with cholesterol but not for other Cho-containing metabolites or proteins. Significant contrast was found between tumor and contralateral normal tissue signals in animals when comparing both the measured saturation transfer signal and a more specific imaging metric. CONCLUSION: We demonstrated specific relayed nuclear Overhauser effects in partially restricted phospholipid phantoms and similar effects in solid brain tumors after correcting for confounding signal contributions, suggesting possible translational applications of this novel molecular imaging method, which we name restricted phospholipid transfer.

Signal Amplification By Reversible Exchange (SABRE) is a new and rapidly developing hyperpolarization technique. The recent discovery of Spin-Lock Induced Crossing SABRE (SLIC-SABRE) shows that high field hyperpolarization transfer techniques developed so far were optimized for singlet spin order that does not coincide with the experimentally produced spin state. Here, we investigate the SLIC-SABRE approach and the most advanced quantitative theoretical SABRE model. It is the goal to achieve the highest possible polarization with SLIC-SABRE at high field using the standard SABRE system, IrIMes catalyst with pyridine. We demonstrate the accuracy of SABRE model describing the effects of various physical parameters such as the amplitude and frequency of the radio-frequency field, and the effects of chemical parameters such as the exchange rate constants. The combined use of experiments and theory allows to determine the effective lifetime of SABRE-complex. Furthermore, the entropy and enthalpy of the SABRE-complex dissociation reaction based on the temperature dependence of SLIC-SABRE signal can be accessed. We show, for the first time, that this SLIC-SABRE model can be useful for the evaluation of the chemical exchange parameters that are very important for the production of highly polarized contrast agents via SABRE.

We report synthesis of (15)N-3-(19)F-pyridine via Zincke salt formation with the overall 35% yield and 84% (15)N isotopic purity. Hyperpolarization studies of Signal Amplification by Reversible Exchange (SABRE) and SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) were performed to investigate the mechanism of polarization transfer from parahydrogen-derived hydride protons to (19)F nucleus in milli-Tesla and micro-Tesla magnetic field regimes in (15)N-3-(19)F-pyridine and (14)N-3-(19)F-pyridine. We found the mismatch between (15)N and (19)F magnetic field hyperpolarization profiles in the micro-Tesla regime indicating that the spontaneous hyperpolarization process likely happens directly from parahydrogen-derived hydride protons to (19)F nucleus without spin-relaying via (15)N site. In case of SABRE magnetic field regime (milli-Tesla magnetic field range), we found that magnetic field profiles for (1)H and (19)F hyperpolarization are very similar, and (19)F polarization levels are significantly lower than (1)H SABRE polarization levels and lower than (19)F SABRE-SHEATH (i.e. obtained at micro-Tesla magnetic field) polarization levels. Our findings support the hypothesis that in milli-Tesla magnetic field regime, the process of (19)F nuclei hyperpolarization is relayed via protons of substrate, and therefore is very inefficient. These findings are important in the context of improvement of the hyperpolarization hardware and rational design of the hyperpolarized molecular probes.

We show the simultaneous generation of hyperpolarized (13)C-labeled acetate and (15)N-labeled imidazole following spin-relay of hyperpolarization and hydrolysis of the acetyl moiety on 1-(13)C-(15)N(2)-acetylimidazole. Through SABRE-SHEATH (Signal Amplification by Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei), transfer of spin order occurs from parahydrogen to acetylimidazole (15)N atoms and the acetyl (13)C site (~263-fold enhancement), giving rise to relatively long hyperpolarization lifetimes at 0.3 T (T(1) ~52 s and ~149 s for (13)C and (15)N, respectively). Immediately following polarization transfer, the (13)C-labeled acetyl group is hydrolytically cleaved to produce hyperpolarized (13)C-acetate/acetic acid (~140-fold enhancement) and (15)N-imidazole (~180-fold enhancement), the former with a (13)C T(1) of ~14 s at 0.3 T. Straight-forward synthetic routes, efficient spin-relay of SABRE hyperpolarization, and facile bond cleavage open a door to the cheap and rapid generation of long-lived hyperpolarized states within a wide range of molecular targets—including biologically relevant carboxylic acid derivatives—for metabolic and pH imaging.

We report a simple and effective method to remove IrIMes homogeneous polarization transfer catalysts from solutions where NMR Signal Amplification By Reversible Exchange (SABRE) has been performed, while leaving intact the substrate’s hyperpolarized state. Following microTesla SABRE hyperpolarization of (15)N spins in metronidazole, addition of SiO(2) microparticles functionalized with 3-mercaptopropyl or 2-mercaptoethyl ethyl sulfide moieties provides removal of the catalyst from solution well within the hyperpolarization decay time at 0.3 T (T(1)>3 mins)—and enabling transfer to 9.4 T for detection of enhanced (15)N signals in the absence of catalyst within the NMR-detection region. Successful catalyst removal from solution is supported by the inability to “re-hyperpolarize” (15)N spins in subsequent attempts, as well as by (1)H NMR and ICP-MS. Record-high (15)N nuclear polarization of up to ~34% was achieved, corresponding to >100,000-fold enhancement at 9.4 T, and approximately 5/6(th) of the (15)N hyperpolarization is retained after ~20-second-long purification procedure. Taken together, these results help pave the way for future studies involving in vivo molecular imaging using agents hyperpolarized via rapid and inexpensive parahydrogen-based methods.

The successful transfer of para-hydrogen-induced polarization to 15N spins using heterogeneous catalysts in aqueous solutions was demonstrated. Hydrogenation of a synthesized unsaturated 15N-labeled precursor (neurine) with parahydrogen (p-H2) over Rh/TiO2 heterogeneous catalysts yielded a hyperpolarized structural analogue of choline. As a result, 15N polarization enhancements of over 2 orders of magnitude were achieved for the 15N-labeled ethyltrimethylammonium ion product in deuterated water at elevated temperatures. Enhanced 15N NMR spectra were successfully acquired at 9.4 and 0.05 T. Importantly, long hyperpolarization lifetimes were observed at 9.4 T, with a 15N T1 of ∼6 min for the product molecules, and the T1 of the deuterated form exceeded 8 min. Taken together, these results show that this approach for generating hyperpolarized species with extended lifetimes in aqueous, biologically compatible solutions is promising for various biomedical applications.

© 2020 Elsevier Inc. Spin-exchange optical pumping (SEOP) can enhance the NMR sensitivity of noble gases by up to five orders of magnitude at Tesla-strength magnetic fields. SEOP-generated hyperpolarised (HP) 129Xe is a promising contrast agent for lung imaging but an ongoing barrier to widespread clinical usage has been economical production of sufficient quantities with high 129Xe polarisation. Here, the ‘standard model’ of SEOP, which was previously used in the optimisation of continuous-flow 129Xe polarisers, is modified for validation against two Xe-rich stopped-flow SEOP datasets. We use this model to examine ways to increase HP Xe production efficiency in stopped-flow 129Xe polarisers and provide further insight into the underlying physics of Xe-rich stopped-flow SEOP at high laser fluxes.

We report a systematic study of relaxation dynamics of hyperpolarized (HP) propane and HP propane-d(6) prepared by heterogeneous pairwise parahydrogen addition to propylene and propylene-d(6) respectively. Long-lived spin states (LLS) created for these molecules at the low magnetic field of 0.0475 T were employed for this study. The parahydrogen-induced overpopulation of a HP propane LLS decays exponentially with time constant (T(LLS)) approximately 3-fold greater than the corresponding T(1) values. Both T(LLS) and T(1) increase linearly with propane pressure in the range from 1 atm (the most biomedically relevant conditions for pulmonary MRI) to 5 atm. The T(LLS) value of HP propane gas at 1 atm is ~3 s. Deuteration of the substrate (propylene-d(6)) yields hyperpolarized propane-d(6) gas with T(LLS) values approximately 20% shorter than those of hyperpolarized fully protonated propane gas, indicating that deuteration does not benefit the lifetime of the LLS HP state. The use of pH(2) or Xe/N(2) buffering gas during heterogeneous hydrogenation reaction (leading to production of 100% HP propane (no buffering gas) versus 43% HP propane gas (with 57% buffering gas) composition mixtures) results in (i) no significant changes in T(1), (ii) decrease of T(LLS) values (by 35±7% and 8±7% respectively); and (iii) an increase of the polarization levels of HP propane gas with a propane concentration decrease (by 1.6±0.1-fold and 1.4±0.1-fold respectively despite the decrease in T(LLS), which leads to disproportionately greater polarization losses during HP gas transport). Moreover, we demonstrate the feasibility of HP propane cryo-collection (which can be potentially useful for preparing larger amounts of concentrated HP propane, when buffering gas is employed), and T(LLS) of liquefied HP propane reaches 14.7 seconds, which is greater than the T(LLS) value of HP propane gas at any pressure studied. Finally, we have explored the utility of using a partial Spin-Lock Induced Crossing (SLIC) radio frequency (RF) pulse sequence for converting the overpopulated LLS into observable (1)H nuclear magnetization at low magnetic field. We find that (i) the bulk of the overpopulated LLS is retained even when the optimal or near-optimal values of SLIC pulse duration are employed, and (ii) the overpopulated LLS of propane is also relatively immune to strong RF pulses—thereby, indicating that LLS is highly suitable as a spin-polarization reservoir in the context of NMR/MRI detection applications. The presented findings may be useful for improving the levels of polarization of HP propane produced by HET-PHIP via the use of an inert buffer gas; increasing the lifetime of the HP state during preparation and storage; and developing efficient approaches for ultrafast MR imaging of HP propane in the context of biomedical applications of HP propane gas, including its potential use as an inhalable contrast agent.

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.

We report on an extension of the QUASi-Resonance (QUASR) pulse sequence used for Signal Amplification by Reversible Exchange (SABRE), showing that we may target distantly J-coupled (19)F-spins. Polarization transfer from the parahydrogen-derived hydrides to the (19)F nucleus is accomplished via weak five-bond J-couplings using a shaped QUASi-Resonance (QUASR) radio-frequency pulse at a 0.05 T magnetic field. The net result is the direct generation of hyperpolarized (19)F z-magnetization, derived from the parahydrogen singlet order. An accumulation of (19)F polarization on the free ligand is achieved with subsequent repetition of this pulse sequence. The hyperpolarized (19)F signal exhibits clear dependence on the pulse length, irradiation frequency, and delay time in a manner similar to that reported for (15)N QUASR-SABRE. Moreover, the hyperpolarized (19)F signals of 3-(19)F-(14)N-pyridine and 3-(19)F-(15)N-pyridine isotopologues are similar, suggesting (i) that polarization transfer via QUASR-SABRE is irrespective of the nitrogen isotopologue, and (ii) the presence or absence of the spin-1/2 (15)N nucleus has no impact on the efficiency of QUASR-SABRE polarization transfer. Although optimization of polarization transfer efficiency to (19)F (P(19F)~0.1%) was not the goal of this study, we show that high-field SABRE can be efficient and broadly applicable for direct hyperpolarization of (19)F spins.

(13)C-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 (1)H and (13)C 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 (1)H and (13)C nuclei, respectively, in CD(3)OD solutions. Allyl pyruvate and ethyl acetate were also hyperpolarized in aqueous phase using homogeneous hydrogenation with parahydrogen over water-soluble rhodium catalyst. (13)C polarization of 0.82% and 2.1% was obtained for allyl pyruvate and ethyl acetate, respectively. (13)C-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.

NMR hyperpolarization of uniformly (15)N-labeled metronidazole-(15)N(3) is demonstrated using SABRE-SHEATH (Signal Amplification by Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). In this antibiotic, a (15)NO(2) group is hyperpolarized via spin relays created by (15)N spins in metronidazole-(15)N(3), and the polarization is transferred from parahydrogen-derived hydrides over six chemical bonds. This efficient spin-relayed mechanism of polarization transfer is supported by measurements of polarization dynamics and T(1) relaxation in micro-Tesla magnetic fields. In less than a minute of parahydrogen bubbling at ~0.4 μT, a high level of nuclear spin polarization P(15N) of ~16% is achieved on all three (15)N sites of metronidazole-(15)N(3) at up to ~41 mM concentration. This product of (15)N polarization and concentration of (15)N spins is ~6-fold better than any previous value for (15)N SABRE-derived hyperpolarization. At 1.4 T, the hyperpolarized state of the (15)NO(2) group of this antibiotic persists for tens of minutes (T(1)~10 min), in part because its (15)N spin has no detectable spin-spin couplings with protons of the molecule. A novel synthesis achieving robust uniform (15)N enrichment of metronidazole is reported with 15% yield over three steps. This synthetic approach should be suitable for preparation of other (15)N-labeled nitroimidazole derivatives, potentially enabling a wide range of in vivo metabolic probes from hypoxia sensing to theranostic imaging.

Signal Amplification By Reversible Exchange (SABRE) is an inexpensive, fast, and even continuous hyperpolarization technique that uses para-hydrogen as hyperpolarization source. However, current SABRE faces a number of stumbling blocks for translation to biochemical and clinical settings. Difficulties include inefficient polarization in in water, relatively short lived 1H-polarization, and relatively limited substrate scope. Here we use a water soluble polarization transfer catalyst to hyperpolarize nitrogen-15 in a variety of molecules with SABRE-SHEATH (SABRE in Shield Enables Alignment Transfer to Heteronuclei). This strategy works in pure H2O or D2O solutions, on substrates that could not be hyperpolarized in traditional 1H-SABRE experiments, and we record 15N T1 relaxation times of up to 2 min.

Parahydrogen-induced polarization (PHIP) is an NMR hyperpolarization technique that increases nuclear spin polarization by orders of magnitude, and it is particularly well-suited to study hydrogenation reactions. However, the use of high-field NMR spectroscopy is not always possible, especially in the context of potential industrial-scale reactor applications. On the other hand, the direct low-field NMR detection of reaction products with enhanced nuclear spin polarization is challenging due to near complete signal cancellation from nascent parahydrogen protons. We show that hydrogenation products prepared by PHIP can be irradiated with weak (on the order of spin–spin couplings of a few hertz) alternating magnetic field (called Spin-Lock Induced Crossing or SLIC) and consequently efficiently detected at low magnetic field (e.g., 0.05 T used here) using examples of several types of organic molecules containing a vinyl moiety. The detected hyperpolarized signals from several reaction products at tens of millimolar concentrations were enhanced by 10000-fold, producing NMR signals an order of magnitude greater than the background signal from protonated solvents.

An open-source hyperpolarizer producing (13)C hyperpolarized contrast agents using parahydrogen induced polarization (PHIP) for biomedical and other applications is presented. This PHIP hyperpolarizer utilizes an Arduino microcontroller in conjunction with a readily modified graphical user interface written in the open-source processing software environment to completely control the PHIP hyperpolarization process including remotely triggering an NMR spectrometer for efficient production of payloads of hyperpolarized contrast agent and in situ quality assurance of the produced hyperpolarization. Key advantages of this hyperpolarizer include: (i) use of open-source software and hardware seamlessly allowing for replication and further improvement as well as readily customizable integration with other NMR spectrometers or MRI scanners (i.e., this is a multiplatform design), (ii) relatively low cost and robustness, and (iii) in situ detection capability and complete automation. The device performance is demonstrated by production of a dose (∼2-3 mL) of hyperpolarized (13)C-succinate with %P13C ∼ 28% and 30 mM concentration and (13)C-phospholactate at %P13C ∼ 15% and 25 mM concentration in aqueous medium. These contrast agents are used for ultrafast molecular imaging and spectroscopy at 4.7 and 0.0475 T. In particular, the conversion of hyperpolarized (13)C-phospholactate to (13)C-lactate in vivo is used here to demonstrate the feasibility of ultrafast multislice (13)C MRI after tail vein injection of hyperpolarized (13)C-phospholactate in mice.

Two synthetic strategies are investigated for the preparation of water-soluble iridium-based catalysts for NMR signal amplification by reversible exchange (SABRE). In one approach, PEGylation of a variant N-heterocyclic carbene provided a novel catalyst with excellent water solubility. However, while SABRE-active in ethanol solutions, the catalyst lost activity in >50% water. In a second approach, synthesis of a novel di-iridium complex precursor where the cyclooctadiene (COD) rings have been replaced by CODDA (1,2-dihydroxy-3,7-cyclooctadiene) leads to the creation of a catalyst [IrCl(CODDA)IMes] that can be dissolved and activated in water—enabling aqueous SABRE in a single step, without need for either an organic cosolvent or solvent removal followed by aqueous reconstitution. The potential utility of the CODDA catalyst for aqueous SABRE is demonstrated with the ∼(−)32-fold enhancement of 1H signals of pyridine in water with only 1 atm of parahydrogen.

Scalable and versatile methodology for production of vinylated carboxylic compounds with 13C isotopic label in C1 position is described. It afforded robust synthesis of vinyl acetate-1-13C, which is a precursor for preparation of 13C hyperpolarized ethyl acetate-1-13C, which provides a convenient vehicle for potential in vivo delivery of hyperpolarized acetate to probe metabolism in living organisms. Kinetics of vinyl acetate molecular hydrogenation and polarization transfer from parahydrogen to 13C via magnetic field cycling were investigated. Nascent proton nuclear spin polarization (%PH) of ~3.3% and carbon-13 polarization (%P13C) of ~1.8% were achieved in ethyl acetate utilizing 50% parahydrogen corresponding to ~50% polarization transfer efficiency. The use of nearly 100% parahydrogen and the improvements of %PH of parahydrogen-nascent protons will likely enable production of 13C hyperpolarized contrast agents with P13C of 20–50% in seconds using presented here chemistry for preparation of metabolically relevant precursors. Hyperpolarized in this fashion 13C contrast agents can be employed for ultra-fast molecular imaging, the feasibility of which is presented here. A series of 3D images was acquired using 13C hyperpolarized ethyl acetate-1-13C with high spatial (0.5 ×0.5×4 mm3) and temporal (~2.5 s) resolution.

Proton magnetic resonance imaging (1H MRI) of gases can potentially enable functional lung imaging to probe gas ventilation and other functions. Here, 1H MR images of hyperpolarized (HP) and thermally polarized propane gas were obtained using ultrashort echo time (UTE) pulse sequence. A 2-dimensional (2D) image of thermally polarized propane gas with ∼0.9 × 0.9 mm2 spatial resolution was obtained in &lt, 2 seconds, showing that even non-HP hydrocarbon gases can be successfully used for conventional proton magnetic resonance imaging. The experiments were also performed with HP propane gas, and high-resolution multislice FLASH 2D images in ∼510 seconds and non-slice-selective 2D UTE MRI images were acquired in ∼2 seconds. The UTE approach adopted in this study can be potentially used for medical lung imaging. Furthermore, the possibility of combining UTE with selective suppression of 1H signals from 1 of the 2 gases in a mixture is shown in this MRI study. The latter can be useful for visualizing industrially important processes where several gases may be present, eg, gas–solid catalytic reactions.

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 γ m = 1 / T 2 ∗ . 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 > > γ m , 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).

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 mm2 field of view (FOV), 32 × 32 matrix size, demonstrating the feasibility of 15 N HF-SABRE molecular imaging with 2.4 × 2.4 mm2 spatial resolution.

We present a simple-to-implement pneumatic sample shuttle for automation of magnetic field cycling and multidimensional NMR. The shuttle system is robust allowing automation of hyperpolarized and non-hyperpolarized measurements, including variable field lifetime measurements, SABRE polarization optimization, and SABRE multidimensional experiments. Relaxation-protected singlet states are evaluated by variable-field T(1) and T(S) measurements. Automated shuttling facilitates characterization of hyperpolarization dynamics, field dependence and polarization buildup rates. Furthermore, reproducible hyperpolarization levels at every shuttling event enables automated 2D hyperpolarized NMR, including the first inverse (15)N/(1)H HSQC. We uncover binding mechanisms of the catalytic species through cross peaks that are not accessible in standard one-dimensional hyperpolarized experiments. The simple design of the shuttling setup interfaced with standard TTL signals allows easy adaptation to any standard NMR magnet.

Here we present the feasibility of NMR Signal Amplification by Reversible Exchange (SABRE) using radio-frequency irradiation at low magnetic field (0.05 T) in the regime, where the chemical shifts of free and catalyst bound species are similar. In SABRE, the (15)N-containing substrate and parahydrogen perform simultaneous chemical exchange on an Iridium hexacoordinate complex. Shaped Spin-Lock Induced Crossing (SLIC) radio-frequency pulse sequence followed by a delay is applied at QUASi-Resonance (QUASR) condition of (15)N spins of (15)N-enriched substrate. As a result of this pulse sequence application, (15)N z-magnetization is created from the spin-order of parahydrogen derived hyperpolarized hydrides. The repetition of the pulse-sequence block consisting of shaped radio-frequency pulse and the delay leads to the build-up of (15)N magnetization. The modulation of this effect by the irradiation frequency, pulse duration and amplitude, delay duration, and the number of pumping cycles was demonstrated. Pyridine-(15)N, acetonitrile-(15)N, metronidazole-(15)N(2)-(13)C(2) substrates were studied representing three classes of compounds (five- and six-membered heterocycles and nitrile) showing the wide applicability of the technique. Metronidazole-(15)N(2)-(13)C(2) is an FDA-approved antibiotic that can be injected in large quantities promising non-invasive and accurate hypoxia sensing. The (15)N hyperpolarization levels attained with QUASR-SABRE on metronidazole-(15)N(2)-(13)C(2) were more than two-fold greater than with SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) demonstrating that QUASR-SABRE can deliver significantly more efficient means of SABRE hyperpolarization.

We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-(13)C-phosphoenolpyruvate and 1-(13)C-phosphoenolpyruvate-d(2) for application in hyperpolarized imaging technology. The 1-(13)C-phosphoenolpyruvate-d(2) was synthesized with 57% overall yield (over two steps), and >98% (2)H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-(13)C-phosphoenolpyruvate. These two unsaturated compounds with C=C bonds were employed for parahydrogen-induced polarization via pairwise parahydrogen addition in aqueous medium. We find that deuteration of 1-(13)C-phosphoenolpyruvate resulted in overall increase of (1)H T(1) of nascent hyperpolarized protons (4.30 ± 0.04 s versus 2.06 ± 0.01 s) and (1)H polarization (~2.5% versus ~0.7%) of the resulting hyperpolarized 1-(13)C-phospholactate. The nuclear spin polarization of nascent parahydrogen-derived protons was transferred to 1-(13)C nucleus via magnetic field cycling procedure. The proton T(1) increase in hyperpolarized deuterated 1-(13)C-phospholactate yielded approximately 30% better (13)C polarization compared to non-deuterated hyperpolarized 1-(13)C-phospholactate. Analysis of T(1) relaxation revealed that deuteration of 1-(13)C-phospholactate may have resulted in approximately 3-fold worse H→(13)C polarization transfer efficiency via magnetic field cycling. Since magnetic field cycling is a key polarization transfer step in the Side-Arm Hydrogenation approach, the presented findings may guide more rationale design of contrast agents using parahydrogen polarization of a broad range of (13)C hyperpolarized contrast agents for molecular imaging employing (13)C MRI. The hyperpolarized 1-(13)C-phospholactate-d(2) is of biomedical imaging relevance because it undergoes in vivo dephosphorylation and becomes (13)C hyperpolarized lactate, which as we show can be detected in the brain using (13)C hyperpolarized MRI; an implication for future imaging of neurodegenerative diseases and dementia.

Hyperpolarized gases revolutionize functional pulmonary imaging. Hyperpolarized propane is a promising emerging contrast agent for pulmonary MRI. Unlike hyperpolarized noble gases, proton-hyperpolarized propane gas can be imaged using conventional MRI scanners with proton imaging capability. Moreover, it is non-toxic odorless anesthetic. Furthermore, propane hyperpolarization can be accomplished by pairwise addition of parahydrogen to propylene. Here, we demonstrate the feasibility of propane hyperpolarization via hydrogenation of cyclopropane with parahydrogen. 1 H propane polarization up to 2.4 % is demonstrated here using 82 % parahydrogen enrichment and heterogeneous Rh/TiO2 hydrogenation catalyst. This level of polarization is several times greater than that obtained with propylene as a precursor under the same conditions despite the fact that direct pairwise addition of parahydrogen to cyclopropane may also lead to formation of propane with NMR-invisible hyperpolarization due to magnetic equivalence of nascent parahydrogen protons in two CH3 groups. NMR-visible hyperpolarized propane demonstrated here can be formed only via a reaction pathway involving cleavage of at least one C-H bond in the reactant molecule. The resulting NMR signal enhancement of hyperpolarized propane was sufficient for 2D gradient echo MRI of ∼5.5 mL phantom with 1×1 mm2 spatial resolution and 64×64 imaging matrix despite relatively low chemical conversion of cyclopropane substrate.

NMR is one of the most versatile and useful physical effects used for human imaging, chemical analysis and the elucidation of molecular structures. Yet, the full potential of NMR is hardly ever used, because only a small fraction of the nuclear spin ensemble is polarized - i.e. aligned with the applied static magnetic field. This fraction is termed nuclear spin polarization P. As a result, no more than a few parts per million of all nuclear spins effectively contribute to the signal in all magnetic fields (B(0)) available for NMR or MRI today. Because P is approximately linear with B(0), a stronger field offers some but limited improvements. Hyperpolarization methods seek other means to increase P and thus the MR signal. A unique source of pure spin order is the spin singlet state of dihydrogen, parahydrogen (pH(2)), which is inherently stable and long-lived. When brought into contact with another molecule, this “spin order on demand” allows enhancing the NMR signal by several orders of magnitude. In contrast to other methods, this process is very fast (seconds) and can take place in the liquid state. Nuclear spin polarization of the order of unity was demonstrated, manifesting as significant NMR and MRI signal enhancement by several orders of magnitude. Considerable progress was made in the past decade in the area of pH(2)-based hyperpolarization techniques for biomedical applications. It is the goal of this review to provide a comprehensive, selective overview of these developments, covering the areas of spin physics, catalysis, instrumentation, contrast agents’ preparation and application.

A systematic experimental study is reported on the polarization transfer to distant spins, which do not directly bind to the polarization transfer complexes employed in Signal Amplification By Reversible Exchange (SABRE) experiments. Both, long-range transfer to protons and long-range transfer to heteronuclei i.e. 13C and 15N are examined. Selective destruction of hyperpolarization on 1H, 13C, and 15N sites is employed, followed by their re-hyperpolarization from neighboring spins within the molecules of interest (pyridine for 1H studies and metronidazole-15N2-13C2 for 13C and 15N studies). We conclude that long-range sites can be efficiently hyperpolarized when a network of spin-½ nuclei enables relayed polarization transfer (i.e. via short-range interactions between sites). In case of proton SABRE in the milli-Tesla regime, a relay network consisting of protons only is sufficient. However, in case 13C and 15N are targeted (i.e. via SABRE in SHield Enables Alignment Transfer to Heteronuclei or SABRE-SHEATH experiment), the presence of a heteronuclear network (e.g. consisting of 15N) enables a relay mechanism that is significantly more efficient than the direct transfer of spin order from para-H2-derived hydrides.

Hyperpolarized forms of 1-13C-acetates and 1-13C-pyruvates are used as diagnostic contrast agents for molecular imaging of many diseases and disorders. Here, we report the synthetic preparation of 1-13C isotopically enriched and pure from solvent acetates and pyruvates derivatized with unsaturated ester moiety. The reported unsaturated precursors can be employed for NMR hyperpolarization of 1-13C-acetates and 1-13C-pyruvates via parahydrogen-induced polarization (PHIP). In this PHIP variant, Side arm hydrogenation (SAH) of unsaturated ester moiety is followed by the polarization transfer from nascent parahydrogen protons to 13C nucleus via magnetic field cycling procedure to achieve hyperpolarization of 13C nuclear spins. This work reports the synthesis of PHIP-SAH precursors: vinyl 1-13C-acetate (55% yield), allyl 1-13C-acetate (70% yield), propargyl 1-13C-acetate (45% yield), allyl 1-13C-pyruvate (60% yield), and propargyl 1-13C-pyruvate (35% yield). Feasibility of PHIP-SAH 13C hyperpolarization was verified by 13C NMR spectroscopy: hyperpolarized allyl 1-13C-pyruvate was produced from propargyl 1-13C-pyruvate with 13C polarization of ∼3.2% in CD3OD and ∼0.7% in D2O. 13C magnetic resonance imaging is demonstrated with hyperpolarized 1-13C-pyruvate in aqueous medium.

Here, we report the production of 13C-hyperpolarized ethyl acetate via heterogeneously catalyzed pairwise addition of parahydrogen to vinyl acetate over TiO2-supported rhodium nanoparticles, followed by magnetic field cycling. Importantly, the hyperpolarization is demonstrated even at the natural abundance of 13C isotope (ca. 1.1%) along with the easiest separation of the catalyst from the hyperpolarized liquid.