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Kinetic studies are vital for gathering mechanistic insights into heterogeneously catalyzed hydrogenation of unsaturated organic compounds (olefins), where the Horiuti-Polanyi mechanism is ubiquitous on metal catalysts. While this mechanism envisions nonpairwise H 2 addition due to the rapid scrambling of surface hydride (H*) species, a pairwise H 2 addition is experimentally encountered, rationalized here based on density functional theory (DFT) simulations for the ethene (C 2 H 4 ) hydrogenation catalyzed by two-dimensional (2D) MXene Mo 2 C(0001) surface and compared to Rh(111) surface. Results show that ethyl (C 2 H 5 *) hydrogenation is the rate-determining step (RDS) on Mo 2 C(0001), yet C 2 H 5 * formation is the RDS on Rh(111), which features a higher reaction rate and contribution from pairwise H 2 addition compared to 2D-Mo 2 C(0001). This qualitatively agrees with the experimental results for propene hydrogenation with parahydrogen over 2D-Mo 2 C 1- x MXene and Rh/TiO 2 . However, DFT results imply that pairwise selectivity should be negligible owing to the facile H* diffusion on both surfaces, not affected by H* nor C 2 H 4 * coverages. DFT results also rule out the Eley-Rideal mechanism appreciably contributing to pairwise addition. The measurable contribution of the pairwise hydrogenation pathway operating concurrently with the dominant nonpairwise one is proposed to be due to the dynamic site blocking at higher adsorbate coverages or another mechanism that would drastically limit the diffusion of H* adatoms., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

NMR hyperpolarization dramatically improves the detection sensitivity of magnetic resonance through the increase in nuclear spin polarization. Because of the sensitivity increase by several orders of magnitude, additional applications have been unlocked, including imaging of gases in physiologically relevant conditions. Hyperpolarized 129 Xe gas recently received FDA approval as the first inhalable gaseous MRI contrast agent for clinical functional lung imaging of a wide range of pulmonary diseases. However, production and utilization of hyperpolarized 129 Xe gas faces a number of translational challenges including the high cost and complexity of contrast agent production and imaging using proton-only (i.e., conventional) clinical MRI scanners, which are typically not suited to scan 129 Xe nuclei. As a solution to circumvent the translational challenges of hyperpolarized 129 Xe, we have recently demonstrated the feasibility of a simple and cheap process for production of proton-hyperpolarized propane gas contrast agent using ultralow-cost disposable production equipment and demonstrated the feasibility of lung ventilation imaging using hyperpolarized propane gas in excised pig lungs. However, previous pilot studies have concluded that the hyperpolarized state of propane gas decays very fast with an exponential decay T 1 constant of ∼0.8 s at 1 bar (physiologically relevant pressure); moreover, the previously reported production rates were too slow for potential clinical utilization. Here, we investigate the feasibility of high-capacity production of hyperpolarized butane gas via heterogeneous parahydrogen-induced polarization using Rh nanoparticle-based catalyst utilizing butene gas as a precursor for parahydrogen pairwise addition. We demonstrate a remarkable result: the lifetime of the hyperpolarized state can be nearly doubled compared to that of propane ( T 1 of ∼1.6 s and long-lived spin-state T S of ∼3.8 s at clinically relevant 1 bar pressure). Moreover, we demonstrate a production speed of up to 0.7 standard liters of hyperpolarized gas per second. These two synergistic developments pave the way to biomedical utilization of proton -hyperpolarized gas media for ventilation imaging. Indeed, here we demonstrate the feasibility of phantom imaging of hyperpolarized butane gas in Tedlar bags and also the feasibility of subsecond 2D ventilation gas imaging in excised rabbit lungs with 1.6 × 1.6 mm 2 in-plane resolution using a clinical MRI scanner. The demonstrated results have the potential to revolutionize functional pulmonary imaging with a simple and inexpensive on-demand production of proton -hyperpolarized gas contrast media, followed by visualization on virtually any MRI scanner, including emerging bedside low-field MRI scanner technology., Competing Interests: The authors declare the following competing financial interest(s): E.Y.C. and B.M.G. declare a stake of ownership in XeUS Technologies LTD. E.Y.C. serves on the Scientific Advisory Board (SAB) and declares a stake of ownership in Vizma Life Sciences., (© 2024 The Authors. Co-published by Nanjing University and American Chemical Society.)

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. This process is called Signal Amplification By Reversible Exchange (SABRE). Signal intensity gains of several orders of magnitude can thus be created for various compounds in seconds. The chemical exchange processes play a defining role in controlling the efficiency of SABRE because the lifetime of the complex must match the spin-spin couplings. Here, we show how analyte dissociation rates in the key model substrates pyridine (the simplest six-membered heterocycle), 4-aminopyridine (a drug), and nicotinamide (an essential vitamin biomolecule) can be examined. This is achieved for the most widely employed SABRE motif that is based on IrIMes-derived catalysts by 1 H 1D and 2D exchange NMR spectroscopy techniques. Several kinetic models are evaluated for their accuracy and simplicity. By incorporating variable temperature analysis, the data yields key enthalpies and entropies of activation that are critical for understanding the underlying SABRE catalyst properties and subsequently optimizing behavior through rational chemical design. While several studies of chemical exchange in SABRE have been reported, this work also aims to establish a toolkit on how to quantify chemical exchange in SABRE and ensure that data can be compared reliably.

Metronidazole is a prospective hyperpolarized MRI contrast agent with potential hypoxia sensing utility for applications in cancer, stroke, neurodegenerative diseases, etc. We demonstrate a pilot procedure for production of ∼30 mM hyperpolarized [ 15 N 3 ]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three 15 N sites achieved in less than 2 min. The 15 N polarization T 1 of ∼12 min is reported for the 15 NO 2 group at the clinically relevant field of 1.4 T in the aqueous phase, demonstrating a remarkably long lifetime of the hyperpolarized state. The produced aqueous solution of [ 15 N 3 ]metronidazole that contained only ∼100 μM of residual Ir was deemed biocompatible via validation through the MTT colorimetric test for assessing cell metabolic activity using human embryotic kidney HEK293T cells. This low-cost and ultrafast hyperpolarization procedure represents a major advance for the production of a biocompatible HP [ 15 N 3 ]metronidazole (and potentially other hyperpolarized drugs) formulation for MRI sensing applications.

We present an integrated, open-source device for parahydrogen-based hyperpolarization processes in the microtesla field regime with a cost of components of less than $7000. The device is designed to produce a batch of 13 C and 15 N hyperpolarized (HP) compounds via hydrogenative or non-hydrogenative parahydrogen-induced polarization methods that employ microtesla magnetic fields for efficient polarization transfer of parahydrogen-derived spin order to X-nuclei (e.g., 13 C and 15 N). The apparatus employs a layered structure (reminiscent of a Russian doll "Matryoshka") that includes a nonmagnetic variable-temperature sample chamber, a microtesla magnetic field coil (operating in the range of 0.02-75 microtesla), a three-layered mu-metal shield (to attenuate the ambient magnetic field), and a magnetic shield degaussing coil placed in the overall device enclosure. The gas-handling manifold allows for parahydrogen-gas flow and pressure control (up to 9.2 bar of total parahydrogen pressure). The sample temperature can be varied either using a water bath or a PID-controlled heat exchanger in the range from -12 to 80 °C. This benchtop device measures 62 cm (length) × 47 cm (width) × 47 cm (height), weighs 30 kg, and requires only connections to a high-pressure parahydrogen gas supply and a single 110/220 VAC power source. The utility of the device has been demonstrated using an example of parahydrogen pairwise addition to form HP ethyl [1- 13 C]acetate ( P 13C = 7%, [c] = 1 M). Moreover, the Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) technique was employed to demonstrate efficient hyperpolarization of 13 C and 15 N spins in a wide range of biologically relevant molecules, including [1- 13 C]pyruvate ( P 13C = 14%, [c] = 27 mM), [1- 13 C]-α-ketoglutarate ( P 13C = 17%), [1- 13 C]ketoisocaproate ( P 13C = 18%), [ 15 N 3 ]metronidazole ( P 15N = 13%, [c] = 20 mM), and others. While the vast majority of the utility studies have been performed in standard 5 mm NMR tubes, the sample chamber of the device can accommodate a wide range of sample container sizes and geometries of up to 1 L sample volume. The device establishes an integrated, simple, inexpensive, and versatile equipment gateway needed to facilitate parahydrogen-based hyperpolarization experiments ranging from basic science to preclinical applications; indeed, detailed technical drawings and a bill of materials are provided to support the ready translation of this design to other laboratories.

13 C hyperpolarized pyruvate is an emerging MRI contrast agent for sensing molecular events in cancer and other diseases with aberrant metabolic pathways. This metabolic contrast agent can be produced via several hyperpolarization techniques. Despite remarkable success in research settings, widespread clinical adoption faces substantial roadblocks because the current sensing technology utilized to sense this contrast agent requires the excitation of 13 C nuclear spins that also need to be synchronized with MRI field gradient pulses. Here, we demonstrate sensing of hyperpolarized allyl [1- 13 C]pyruvate via the stimulated emission of radiation that mitigates the requirements currently blocking broader adoption. Specifically, 13 C Radiofrequency Amplification by Stimulated Emission of Radiation ( 13 C RASER) was obtained after pairwise addition of parahydrogen to a pyruvate precursor, detected in a commercial inductive detector with a quality factor ( Q ) of 32 for sample concentrations as low as 0.125 M with 13 C polarization of 4%. Moreover, parahydrogen-induced polarization allowed for the preparation of a mixture of ketone and hemiketal forms of hyperpolarized allyl [1- 13 C]pyruvate, which are separated by 10 ppm in 13 C NMR spectra. This is a good model system to study the simultaneous 13 C RASER signals of multiple 13 C species. This system models the metabolic production of hyperpolarized [1- 13 C]lactate from hyperpolarized [1- 13 C]pyruvate, which has a similar chemical shift difference. Our results show that 13 C RASER signals can be obtained from both species simultaneously when the emission threshold is exceeded for both species. On the other hand, when the emission threshold is exceeded only for one of the hyperpolarized species, 13 C stimulated emission is confined to this species only, therefore enabling the background-free detection of individual hyperpolarized 13 C signals. The reported results pave the way to novel sensing approaches of 13 C hyperpolarized pyruvate, potentially unlocking hyperpolarized 13 C MRI on virtually any MRI system─an attractive vision for the future molecular imaging and diagnostics.

Hyperpolarized magnetic resonance imaging (MRI) contrast agents are revolutionizing the field of biomedical imaging. Hyperpolarized Xe-129 was recently FDA approved as an inhalable MRI contrast agent for functional lung imaging sensing. Despite success in research settings, modern Xe-129 hyperpolarizers are expensive (up to $1M), large, and complex to site and operate. Moreover, Xe-129 sensing requires specialized MRI hardware that is not commonly available on clinical MRI scanners. Here, we demonstrate that proton-hyperpolarized propane gas can be produced on demand using a disposable, hand-held, clinical-scale hyperpolarizer via parahydrogen-induced polarization, which relies on parahydrogen as a source of hyperpolarization. The device consists of a heterogeneous catalytic reactor connected to a gas mixture storage can containing pressurized hyperpolarization precursors: propylene and parahydrogen (10 bar total pressure). Once the built-in flow valve of the storage can is actuated, the precursors are ejected from the can into a reactor, and a stream of hyperpolarized propane gas is ejected from the reactor. Robust operation of the device is demonstrated for producing proton sensing polarization of 1.2% in a wide range of operational pressures and gas flow rates. We demonstrate that the propylene/parahydrogen gas mixture can retain potency for days in the storage can with a monoexponential decay time constant of 6.0 ± 0.5 days, which is limited by the lifetime of the parahydrogen singlet spin state in the storage container. The utility of the produced sensing agent is demonstrated for phantom imaging on a 3 T clinical MRI scanner located 100 miles from the agent/device preparation site and also for ventilation imaging of excised pig lungs using a 0.35 T clinical MRI scanner. The cost of the device components is less than $35, which we envision can be reduced to less than $5 for mass-scale production. The hyperpolarizer device can be reused, recycled, or disposed.

Magnetic resonance techniques are successfully utilized in a broad range of scientific disciplines and in various practical applications, with medical magnetic resonance imaging being the most widely known example. Currently, both fundamental and applied magnetic resonance are enjoying a major boost owing to the rapidly developing field of spin hyperpolarization. Hyperpolarization techniques are able to enhance signal intensities in magnetic resonance by several orders of magnitude, and thus to largely overcome its major disadvantage of relatively low sensitivity. This provides new impetus for existing applications of magnetic resonance and opens the gates to exciting new possibilities. In this review, we provide a unified picture of the many methods and techniques that fall under the umbrella term "hyperpolarization" but are currently seldom perceived as integral parts of the same field. Specifically, before delving into the individual techniques, we provide a detailed analysis of the underlying principles of spin hyperpolarization. We attempt to uncover and classify the origins of hyperpolarization, to establish its sources and the specific mechanisms that enable the flow of polarization from a source to the target spins. We then give a more detailed analysis of individual hyperpolarization techniques: the mechanisms by which they work, fundamental and technical requirements, characteristic applications, unresolved issues, and possible future directions. We are seeing a continuous growth of activity in the field of spin hyperpolarization, and we expect the field to flourish as new and improved hyperpolarization techniques are implemented. Some key areas for development are in prolonging polarization lifetimes, making hyperpolarization techniques more generally applicable to chemical/biological systems, reducing the technical and equipment requirements, and creating more efficient excitation and detection schemes. We hope this review will facilitate the sharing of knowledge between subfields within the broad topic of hyperpolarization, to help overcome existing challenges in magnetic resonance and enable novel applications.

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. In this work, we polarized 15 N nuclei of [ 15 N 1 ]fampridine (a drug used for the treatment of multiple sclerosis) to the level of 4% in nuclear magnetic resonance (NMR) experiments and 0.7% in MRI studies using spin-lock-induced crossing combined with signal amplification by reversible exchange. Consequently, three-dimensional 15 N MRI of the hyperpolarized 15 N-labeled drug was acquired in 0.1 s with a signal-to-noise ratio of 70. In addition, the NMR signal enhancements for 15 N-enriched fampridine and fampridine with a natural abundance of 15 N nuclei were compared and an explanation for their difference was proposed.

Hyperpolarized ( i.e. , 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 19 F and 31 P) in a wide range of molecules. The magnitude of the effect correlates with the T 1 relaxation time of the target nuclear spins. A series of control experiments validate the through-space dipolar mechanism of the RASER-assisted polarization transfer between the parahydrogen-polarized compound and to-be-hyperpolarized nuclei of the target molecule. Frequency-selective saturation of the RASER-active resonances was used to control the RASER and the amplitude of spontaneous polarization transfer. Spin dynamics simulations support our experimental RASER studies. The enhanced NMR sensitivity may benefit various NMR applications such as mixture analysis, metabolomics, and structure determination.

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 ( P ), fast reaction, and low cost with the broad applicability of polarization transfer via proton exchange. We identified the system propargyl alcohol + pH 2 → allyl alcohol to yield 1 H polarization in excess of P ≈ 13% by using only 50% enriched pH 2 at a pressure of ≈1 bar. The polarization was then successfully relayed via proton exchange from allyl alcohol to various target molecules. The polarizations of water and alcohols (as target molecules) approached P ≈ 1% even at high molar concentrations of 100 mM. Lactate, glucose, and pyruvic acid were also polarized, but to a lesser extent. Several potential improvements of the methodology are discussed. Thus, the parahydrogen-induced hyperpolarization relayed via proton exchange (PHIP-X) is a promising approach to polarize numerous molecules which participate in proton exchange and support new applications for magnetic resonance.

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

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 13 C-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 13 C 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 13 C polarization of ethyl acetate-1- 13 C, i.e ., the product of pairwise addition of parahydrogen to vinyl acetate-1- 13 C, 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 1 H to 13 C 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 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 that (i) 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 19 F ≈ 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.

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.

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., 129 Xe) 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.

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) showed 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 investigated the SLIC-SABRE approach and the most advanced quantitative theoretical SABRE model to date. Our goal is to achieve the highest possible polarization with SLIC-SABRE at high field using the standard SABRE system, IrIMes catalyst with pyridine. We demonstrated the accuracy of the 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. By fitting the model to the experimental data, the effective life time of the SABRE complex was estimated, as well as the entropy and enthalpy of the complex-dissociation reaction. 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 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.

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 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.

Hyperpolarized forms of 1- 13 C-acetates and 1- 13 C-pyruvates are used as diagnostic contrast agents for molecular imaging of many diseases and disorders. Here, we report the synthetic preparation of 1- 13 C 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- 13 C-acetates and 1- 13 C-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 13 C nucleus via magnetic field cycling procedure to achieve hyperpolarization of 13 C nuclear spins. This work reports the synthesis of PHIP-SAH precursors: vinyl 1- 13 C-acetate (55% yield), allyl 1- 13 C-acetate (70% yield), propargyl 1- 13 C-acetate (45% yield), allyl 1- 13 C-pyruvate (60% yield), and propargyl 1- 13 C-pyruvate (35% yield). Feasibility of PHIP-SAH 13 C hyperpolarization was verified by 13 C NMR spectroscopy: hyperpolarized allyl 1- 13 C-pyruvate was produced from propargyl 1- 13 C-pyruvate with 13 C polarization of ∼3.2% in CD 3 OD and ∼0.7% in D 2 O. 13 C magnetic resonance imaging is demonstrated with hyperpolarized 1- 13 C-pyruvate in aqueous medium., Competing Interests: The authors declare no competing financial interest.

Parahydrogen can be used in catalytic hydrogenations to achieve substantial enhancement of NMR signals of the reaction products and in some cases of the reaction reagents as well. The corresponding nuclear spin hyperpolarization technique, known as parahydrogen-induced polarization (PHIP), has been applied to boost the sensitivity of NMR spectroscopy and magnetic resonance imaging by several orders of magnitude. The catalyst properties are of paramount importance for PHIP because the addition of parahydrogen to a substrate must be pairwise. This requirement significantly narrows down the range of the applicable catalysts. Herein, we study an efficient silica-supported vanadium oxo organometallic complex (VCAT) in hydrogenation and dehydrogenation reactions in terms of efficient PHIP production. This is the first example of group 5 catalyst used to produce PHIP. Hydrogenations of propene and propyne with parahydrogen over VCAT demonstrated production of hyperpolarized propane and propene, respectively. The achieved NMR signal enhancements were 200-300-fold in the case of propane and 1300-fold in the case of propene. Propane dehydrogenation in the presence of parahydrogen produced no hyperpolarized propane, but instead the hyperpolarized side-product 1-butene was detected. Test experiments of other group 5 (Ta) and group 4 (Zr) catalysts showed a much lower efficiency in PHIP as compared to that of VCAT. The results prove the general conclusion that vanadium-based catalysts and other group 4 and group 5 catalysts can be used to produce PHIP. The hydrogenation/dehydrogenation processes, however, are accompanied by side reactions leading, for example, to C4, C2, and C1 side products. Some of the side products like 1-butene and 2-butene were shown to appear hyperpolarized, demonstrating that the reaction mechanism includes pairwise parahydrogen addition in these cases as well., Competing Interests: The authors declare no competing financial interest.

The ability of frustrated Lewis pairs (FLPs) to activate H 2 is of significant interest for metal-free catalysis. The activation of H 2 is also the key element of parahydrogen-induced polarization (PHIP), one of the nuclear spin hyperpolarization techniques. It is demonstrated that o-phenylene-based ansa-aminoboranes (AABs) can produce 1 H nuclear spin hyperpolarization through a reversible interaction with parahydrogen at ambient temperatures. Heteronuclei are useful in NMR and MRI as well because they have a broad chemical shift range and long relaxation times and may act as background-free labels. We report spontaneous formation of 15 N hyperpolarization of the N-H site for a family of AABs. The process is efficient at the high magnetic field of an NMR magnet (7 T), and it provides up to 350-fold 15 N signal enhancements. Different hyperpolarization effects are observed with various AAB structures and in a broad temperature range. Spontaneous hyperpolarization, albeit an order of magnitude weaker than that for 15 N, was also observed for 11 B nuclei.

The Signal Amplification by Reversible Exchange (SABRE) technique employs exchange with singlet-state parahydrogen to efficiently generate high levels of nuclear spin polarization. Spontaneous SABRE has been shown previously to be efficient in the milli-Tesla and micro-Tesla regimes. We have recently demonstrated that high-field SABRE is also possible, where proton sites of molecules that are able to reversibly coordinate to a metal center can be hyperpolarized directly within high-field magnets, potentially offering the convenience of in situ hyperpolarization-based spectroscopy and imaging without sample shuttling. Here, we show efficient polarization transfer from parahydrogen ( para -H 2 ) to the 15 N atoms of imidazole- 15 N 2 and nicotinamide- 15 N achieved via high-field SABRE (HF-SABRE). Spontaneous transfer of spin order from the para -H 2 protons to 15 N atoms at the high magnetic field of an MRI scanner allows one not only to record enhanced 15 N NMR spectra of in situ hyperpolarized biomolecules, but also to perform imaging using conventional MRI sequences. 2D 15 N MRI of high-field SABRE-hyperpolarized imidazole with spatial resolution of 0.3×0.3 mm 2 at 9.4 T magnetic field and a high signal-to-noise ratio (SNR) of ~99 was demonstrated. We show that 1 H MRI of in situ HF-SABRE hyperpolarized biomolecules ( e.g . imidazole- 15 N 2 ) is also feasible. Taken together, these results show that heteronuclear ( 15 N) and 1 H spectroscopic detection and imaging of high-field-SABRE-hyperpolarized molecules are promising tools for a number of emerging applications.

The successful transfer of parahydrogen-induced polarization to 15 N spins using heterogeneous catalysts in aqueous solutions was demonstrated. Hydrogenation of a synthesized unsaturated 15 N-labeled precursor (neurine) with parahydrogen (p-H 2 ) over Rh/TiO 2 heterogeneous catalysts yielded a hyperpolarized structural analog of choline. As a result, 15 N polarization enhancements of over two orders of magnitude were achieved for the 15 N-ethyl trimethyl ammonium ion product in deuterated water at elevated temperatures. Enhanced 15 N NMR spectra were successfully acquired at 9.4 T and 0.05 T. Importantly, long hyperpolarization lifetimes were observed at 9.4 T, with a 15 N T 1 of ~6 min for the product molecules, and the T 1 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., Competing Interests: Notes The authors declare no competing financial interests.

Hyperpolarized (HP) propane produced by the parahydrogen-induced polarization (PHIP) technique has been recently introduced as a promising contrast agent for functional lung magnetic resonance (MR) imaging. However, its short lifetime due to a spin-lattice relaxation time T 1 of less than 1 s in the gas phase is a significant translational challenge for its potential biomedical applications. The previously demonstrated approach for extending the lifetime of the HP propane state through long-lived spin states allows the HP propane lifetime to be increased by a factor of ∼3. Here, we demonstrate that a remarkable increase in the propane hyperpolarization decay time at high magnetic field (7.1 T) can be achieved by its dissolution in deuterated organic solvents (acetone- d 6 or methanol- d 4 ). The approximate values of the HP decay time for propane dissolved in acetone- d 6 are 35.1 and 28.6 s for the CH 2 group and the CH 3 group, respectively (similar values were obtained for propane dissolved in methanol- d 4 ), which are ∼50 times larger than the gaseous propane T 1 value. Furthermore, we show that it is possible to retrieve HP propane from solution to the gas phase with the preservation of hyperpolarization.

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.

The activation and conversion of hydrocarbons is one of the most important challenges in chemistry. Transition-metal ions (V, Cr, Fe, Co, etc.) isolated on silica surfaces are known to catalyze such processes. The mechanisms of these processes are currently unknown but are thought to involve C-H activation as the rate-determining step. Here, we synthesize well-defined Co(II) ions on a silica surface using a metal siloxide precursor followed by thermal treatment under vacuum at 500 °C. We show that these isolated Co(II) sites are catalysts for a number of hydrocarbon conversion reactions, such as the dehydrogenation of propane, the hydrogenation of propene, and the trimerization of terminal alkynes. We then investigate the mechanisms of these processes using kinetics, kinetic isotope effects, isotopic labeling experiments, parahydrogen induced polarization (PHIP) NMR, and comparison with a molecular analog. The data are consistent with all of these reactions occurring by a common mechanism, involving heterolytic C-H or H-H activation via a 1,2 addition across a Co-O bond.

In the present study we analyze the factors which can lower hyperpolarization of fluids produced in a continuous flow regime by the parahydrogen-induced polarization technique. We use the findings of this analysis to examine the flow rate dependence of propane hyperpolarization produced in the heterogeneous propylene hydrogenation by parahydrogen over Rh/TiO2 catalyst. We have estimated the maximum attainable propane (1)H hyperpolarization yield and the corrected percentage of pairwise hydrogen addition in heterogeneous hydrogenation, which was found to be ∼7%. The approach developed for polarization analysis is useful for the optimization of experimental setup and reaction conditions to obtain maximum hyperpolarization for parahydrogen-based catalyst-free continuously generated fluids applicable in biomedical magnetic resonance imaging.

Long-lived spin states of hyperpolarized propane- d 6 gas were demonstrated following pairwise addition of parahydrogen gas to propene- d 6 using heterogeneous parahydrogen-induced polarization (HET-PHIP). Hyperpolarized molecules were synthesized using Rh/TiO 2 solid catalyst with 1.6 nm Rh nanoparticles. Hyperpolarized ( P H ∼ 1%) propane- d 6 was detected at high magnetic field (9.4 T) spectroscopically and by high-resolution 3D gradient-echo MRI (4.7 T) as the gas flowed through the radiofrequency coil with a spatial and temporal resolution of 0.5 × 0.5 × 0.5 mm 3 and 17.7 s, respectively. Stopped-flow hyperpolarized propane- d 6 gas was also detected at 0.0475 T with an observed nuclear spin polarization of P H ∼ 0.1% and a relatively long lifetime with T 1,eff = 6.0 ± 0.3 s. Importantly, it was shown that the hyperpolarized protons of the deuterated product obtained via pairwise parahydrogen addition could be detected directly at low magnetic field. Importantly, the relatively long low-field T 1,eff of HP propane- d 6 gas is not susceptible to paramagnetic impurities as tested by exposure to ∼0.2 atm oxygen. This long lifetime and nontoxic nature of propane gas could be useful for bioimaging applications including potentially pulmonary low-field MRI. The feasibility of high-resolution low-field 2D gradient-echo MRI was demonstrated with 0.88 × 0.88 mm 2 spatial and ∼0.7 s temporal resolution, respectively, at 0.0475 T.

Activation of a catalyst [IrCl(COD)(IMes)] (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene; COD = cyclooctadiene)] for signal amplification by reversible exchange (SABRE) was monitored by in situ hyperpolarized proton NMR at 9.4 T. During the catalyst-activation process, the COD moiety undergoes hydrogenation that leads to its complete removal from the Ir complex. A transient hydride intermediate of the catalyst is observed via its hyperpolarized signatures, which could not be detected using conventional nonhyperpolarized solution NMR. SABRE enhancement of the pyridine substrate can be fully rendered only after removal of the COD moiety; failure to properly activate the catalyst in the presence of sufficient substrate can lead to irreversible deactivation consistent with oligomerization of the catalyst molecules. Following catalyst activation, results from selective RF-saturation studies support the hypothesis that substrate polarization at high field arises from nuclear cross-relaxation with hyperpolarized (1)H spins of the hydride/orthohydrogen spin bath. Importantly, the chemical changes that accompanied the catalyst's full activation were also found to endow the catalyst with water solubility, here used to demonstrate SABRE hyperpolarization of nicotinamide in water without the need for any organic cosolvent--paving the way to various biomedical applications of SABRE hyperpolarization methods.

We demonstrate the feasibility of microscale molecular imaging using hyperpolarized proton and carbon-13 MRI contrast media and low-field (47.5 mT) preclinical scale (38 mm i.d.) 2D magnetic resonance imaging (MRI). Hyperpolarized proton images with 94 × 94 μm(2) spatial resolution and hyperpolarized carbon-13 images with 250 × 250 μm(2) in-plane spatial resolution were recorded in 4-8 s (largely limited by the electronics response), surpassing the in-plane spatial resolution (i.e., pixel size) achievable with micro-positron emission tomography (PET). These hyperpolarized proton and (13)C images were recorded using large imaging matrices of up to 256 × 256 pixels and relatively large fields of view of up to 6.4 × 6.4 cm(2). (13)C images were recorded using hyperpolarized 1-(13)C-succinate-d2 (30 mM in water, %P(13C) = 25.8 ± 5.1% (when produced) and %P(13C) = 14.2 ± 0.7% (when imaged), T1 = 74 ± 3 s), and proton images were recorded using (1)H hyperpolarized pyridine (100 mM in methanol-d4, %P(H) = 0.1 ± 0.02% (when imaged), T1 = 11 ± 0.1 s). Both contrast agents were hyperpolarized using parahydrogen (>90% para-fraction) in an automated 5.75 mT parahydrogen induced polarization (PHIP) hyperpolarizer. A magnetized path was demonstrated for successful transportation of a (13)C hyperpolarized contrast agent (1-(13)C-succinate-d2, sensitive to fast depolarization when at the Earth's magnetic field) from the PHIP polarizer to the 47.5 mT low-field MRI. While future polarizing and low-field MRI hardware and imaging sequence developments can further improve the low-field detection sensitivity, the current results demonstrate that microscale molecular imaging in vivo is already feasible at low (<50 mT) fields and potentially at low (~1 mM) metabolite concentrations.

(1)H NMR signal amplification by reversible exchange (SABRE) was observed for pyridine and pyridine-d5 at 9.4 T, a field that is orders of magnitude higher than what is typically utilized to achieve the conventional low-field SABRE effect. In addition to emissive peaks for the hydrogen spins at the ortho positions of the pyridine substrate (both free and bound to the metal center), absorptive signals are observed from hyperpolarized orthohydrogen and Ir-complex dihydride. Real-time kinetics studies show that the polarization build-up rates for these three species are in close agreement with their respective (1)H T1 relaxation rates at 9.4 T. The results suggest that the mechanism of the substrate polarization involves cross-relaxation with hyperpolarized species in a manner similar to the spin-polarization induced nuclear Overhauser effect. Experiments utilizing pyridine-d5 as the substrate exhibited larger enhancements as well as partial H/D exchange for the hydrogen atom in the ortho position of pyridine and concomitant formation of HD molecules. While the mechanism of polarization enhancement does not explicitly require chemical exchange of hydrogen atoms of parahydrogen and the substrate, the partial chemical modification of the substrate via hydrogen exchange means that SABRE under these conditions cannot rigorously be referred to as a non-hydrogenative parahydrogen induced polarization process.

To date, only metal-containing hydrogenation catalysts have been utilized for producing substantial NMR signal enhancements by means of parahydrogen-induced polarization (PHIP). Herein, we show that metal-free compounds known as molecular tweezers are useful in this respect. It is shown that ansa-aminoborane tweezers QCAT provided (20-30)-fold signal enhancements of parahydrogen-originating hydrogens in (1)H NMR spectra. Nuclear polarization transfer from the polarized hydrogens to (11)B nuclei leads to a 10-fold enhancement in the (11)B NMR spectrum. Moreover, our results indicate that dihydrogen activation by QCAT and CAT tweezers is carried out in a pairwise manner, and PHIP can be used for understanding the activation mechanism in metal-free catalytic systems in general.

A theoretical model of the nuclear spin isomer conversion in C2H4 induced by the intramolecular spin-spin interaction between hydrogen nuclei has been developed. In the ground electronic state, C2H4 has four nuclear spin isomers in contrast to two isomers in the molecules studied so far in this field of research. At the gas pressure of 1 Torr, the rate of conversion between isomers with the nuclear spin symmetries B1u and B2u was found to be 5.2 × 10(-4) s(-1), which coincides within experimental uncertainties with the rate recently measured by Sun et al. (Science 2005, 310, 1938). It was determined that at low gas pressures the conversion is induced mainly by the mixing of only one pair of rotational states. The calculated pressure dependence of the conversion rate predicts that conversion slows down with increasing pressure at pressures higher than 300 Torr.

Herein, we report a novel strategy to engineer an acid-sensitive anticancer theranostic agent using a vector-drug ensemble. The ensemble was synthesized by directly conjugating the linoleic acid (LA)-modified branched polyethyleneimine with a chemotherapeutic drug trifluorothymidine. Linoleic acid residues were grafted onto 25 kDa polyethyleneimine (PEI) by treating PEI with linoleic acid chloroanhydride. 5-Trifluoromethyl-2'-deoxyuridine (trifluorothymidine, TFT) was introduced into LA-PEI conjugate by phosphorylating the conjugate with amidophosphate of trifluorothymidine 5'-monophosphate (pTFT), which had been activated by its conversion into the N,N-dimethylaminopyridine derivative. The extent of mononucleotide analog incorporation in the polymer was regulated by the ratio of pTFT to the polymer during the synthesis. Samples containing 20-70 TFT residues per PEI molecule were obtained. The cytotoxicity of PEI-LA-pTFT conjugates decreased with increasing nucleotide content, as examined using the MTT method. Due to the presence of fluorine atoms, TFT-based conjugates could be detected directly in the animals by (19)F magnetic resonance imaging. In addition, the presence of the amidophosphate group in PEI-LA-pTFT conjugates allowed their detection by in vivo(31)P NMR spectroscopy. Indeed, the (31)P NMR signal of a phosphoramide (δ ~ 12 ppm) was observed in the mouse muscle tissue treated with PEI-LA-pTFT conjugate along with the signals from endogenous phosphorus-containing compounds. At the same time, the use of PEI-LA-pTFT conjugate for chemotherapeutic drug delivery is limited due to the low release of pTFT from the carrier. To enhance the release of the drug from the conjugate in the endosomes, PEI-LA polymer was coupled with urocanic acid (UA), which bears imidazole ring and thus can form an acid-labile P-N bond with pTFT. The PEI-LA-UA-pTFT conjugate containing 30 residues of UA and 40 residues of pTFT was tested against the murine Krebs-II ascites carcinoma, grown as an ascetic tumor. The intraperitoneal injection of the conjugates resulted in prolongation of the animals' life and to the complete disappearance of the tumor after three injections.

Magnetic resonance imaging (MRI) was used to study the impregnation step during the preparation of Ni/gamma-Al(2)O(3) hydrogenation catalysts with Ni(2+) metal ion present in different coordinations. The precursor complexes were [Ni(H(2)O)(6)](2+) and [Ni(edtaH(x))]((2-x)-) (where x = 0, 1, 2 and edta = ethylenediaminetetraacetic acid), representing a nonshielded and a shielded paramagnetic complex, respectively. Due to this shielding effect of the ligands, the dynamics of [Ni(H(2)O)(6)](2+) or [Ni(edtaH(x))]((2-x)-) were visualized applying T(2) or T(1) image contrast, respectively. MRI was applied in a quantitative manner to calculate the [Ni(H(2)O)(6)](2+) concentration distribution after impregnation when it was present alone in the impregnation solution, or together with the [Ni(edtaH(x))]((2-x)-) species. Moreover, the combination of MRI with UV-vis microspectroscopy allowed the visualization of both species with complementary information on the dynamics and adsorption/desorption phenomena within gamma-Al(2)O(3) catalyst bodies. These phenomena yielded nonuniform Ni distributions after impregnation, which are interesting for certain industrial applications.

An MRI-based approach for the thermometry of an operating packed-bed catalytic reactor was implemented. It was employed for the spatially resolved NMR thermometry of the bed of Pd/gamma-Al2O3 catalyst beads in the course of propylene hydrogenation reaction. This was achieved by detecting the spatially resolved axial 1D profiles of the 27Al NMR signal intensity of Al2O3 in the course of the reaction. The experimental results demonstrate a clear correlation between the 27Al NMR signal intensity and the catalyst temperature measured with a thermocouple (25-250 degrees C), and reveal the existence of pronounced temperature gradients along the catalyst bed.

To gain a better understanding of the advection of reaction fronts in a porous medium, we consider the similarities and the differences between the advection of wavefronts in a packed bed and in a flat gap or a pipe. The model calculations are based on the reaction-diffusion-advection equation for cubic autocatalysis, with the flow field in a gap taken into account explicitly. The analysis performed allows us to conclude that, in the "wide gap" limit, i.e., when the ratio of the gap (or pore) width to the front width is large, for the adverse flow in a porous medium one can expect the formation of stationary wavefronts for a wide range of flow velocities, if one takes into account that advection in a porous medium can effectively quench the axial diffusion of an autocatalyst. These predictions are verified experimentally for a non-oscillatory autocatalytic reaction, viz., the oxidation of thiosulfate with chlorite, carried out in a packed bed of glass beads. It is demonstrated for the first time that, in the case of an adverse flow, the stationary wavefronts in the "wide gap" limit are indeed observed for this reaction, and this limit can be achieved by, e.g., increasing the concentrations of the key reactants. We suggest that the observations of stationary wavefronts in the oscillatory Belousov-Zhabotinsky reaction reported earlier can be accounted for in similar terms. The formation of stationary wavefronts in a packed bed is favored owing to the much larger flow dispersion effects (the ratio of the largest flow velocity to the average flow velocity) in a porous medium as compared to flow in a gap or a pipe. Nevertheless, for a correct description of the effects of advection on the wavefront propagation, it is not appropriate to substitute the dispersion coefficient for diffusivity in the reaction-diffusion-advection equation.

Magnetic resonance imaging was used for two-dimensional temperature visualization of chemical waves propagation in the autocatalytic exothermal reaction of thiosulfate oxidation by chlorite. The technique presented is based on the temperature dependence of the water chemical shift. Temperature maps were acquired by employing the TurboFLASH imaging method. The results obtained allow one to judge about directions of buoyancy flows. Two types of convection critical modes in a vertical tube during the wave propagation were detected.

We demonstrate the creation and observation of para-hydrogen-induced polarization in heterogeneous hydrogenation reactions. Wilkinson's catalyst, RhCl(PPh3)3, supported on either modified silica gel or a polymer, is shown to hydrogenate styrene into ethylbenzene and to produce enhanced spin polarizations, observed through NMR, when the reaction was performed with H2 gas enriched in the para spin isomer. Furthermore, gaseous phase para-hydrogenation of propylene to propane with two catalysts, the Wilkinson's catalyst supported on modified silica gel and Rh(cod)(sulfos) (cod = cycloocta-1,5-diene; sulfos = -O3S(C6H4)CH2C(CH2PPh2)3) supported on silica gel, demonstrates heterogeneous catalytic conversion resulting in large spin polarizations. These experiments serve as a direct verification of the mechanism of heterogeneous hydrogenation reactions involving immobilized metal complexes and can be potentially developed into a practical tool for producing catalyst-free fluids with highly polarized nuclear spins for a broad range of hyperpolarized NMR and MRI applications.

Multinuclear magnetic resonance imaging (MRI) is employed as a new noninvasive tool for monitoring supported catalyst preparation by visualizing precursor transport within the porous support. In particular, liquid phase 31P MRI experiments were used to visualize the dynamics of H3PO4 penetration into an alumina pellet and have revealed a strong interaction of H3PO4 with the support. Solid state 31P MRI was applied to map the distribution of the adsorbed phosphate inside the support after its drying. Comparison of the liquid phase and solid phase MRI results confirms the correlation of the phosphate distribution in the liquid phase during impregnation and the phosphate adsorbed on the support. The possibility to monitor the transport of metal atoms within the support by a direct detection of their NMR signal is demonstrated for 195Pt nucleus during impregnation of an alumina pellet with an aqueous solution of H2PtCl6. Other possible strategies for the utilization of MRI to characterize in situ the preparation of supported catalysts and other supported materials are briefly discussed.

This communication reports the first application of NMR imaging to study the progress of a multiphase heterogeneous catalytic reaction in situ. Various stationary regimes of alpha-methylstyrene (AMS) hydrogenation on a single Pt/gamma-Al2O3 catalyst pellet have been investigated. The two-dimensional maps of the liquid-phase distribution within the pellet have been obtained in the course of the catalytic reaction, with the pellet temperature rising up to 185 degrees C. The large liquid-phase concentration gradients have been shown to exist under conditions of liquid AMS evaporation accompanied by its vapor-phase hydrogenation. It has been demonstrated that despite a substantial broadening of the NMR lines of liquids permeating porous solids the quantification of the relative amounts of AMS and the major reaction product cumene with spatial resolution across the pellet is feasible.