15N Hyperpolarization of Metronidazole Antibiotic in Aqueous Media Using Phase-Separated Signal Amplification by Reversible Exchange with Parahydrogen.

Metronidazole is a prospective hyperpolarized MRI contrast agent with potential hypoxia sensing utility for applications in cancer, stroke, neurodegenerative diseases, etc. We demonstrate a pilot procedure for production of ∼30 mM hyperpolarized [15N3]metronidazole in aqueous media by using a phase-separated SABRE-SHEATH hyperpolarization method, with nitrogen-15 polarization exceeding 2.2% on all three 15N sites achieved in less than 2 min. The 15N polarization T1 of ∼12 min is reported for the 15NO2 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 [15N3]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 [15N3]metronidazole (and potentially other hyperpolarized drugs) formulation for MRI sensing applications.

Manipulating stereoselectivity of parahydrogen addition to acetylene to unravel interconversion of ethylene nuclear spin isomers.

Symmetric molecules exist as distinct nuclear spin isomers (NSIMs). A deeper understanding of their properties, including interconversion of different NSIMs, requires efficient techniques for NSIM enrichment. In this work, selective hydrogenation of acetylene with parahydrogen (p-H2) was used to achieve the enrichment of ethylene NSIMs and to study their equilibration processes. The effect of the stereoselectivity of H2 addition to acetylene on the imbalance of ethylene NSIMs was experimentally demonstrated by using three different heterogeneous catalysts (an immobilized Ir complex and two supported Pd catalysts). The interconversion of NSIMs with time during ethylene storage was studied using NMR spectroscopy by reacting ethylene with bromine water, which rendered the p-H2-derived protons in the produced 2-bromoethan(2H)ol (BrEtOD) magnetically inequivalent, thereby revealing the non-equilibrium nuclear spin order of ethylene. A thorough analysis of the shape and transformation of the 1H NMR spectra of hyperpolarized BrEtOD allowed us to reveal the initial distribution of produced ethylene NSIMs and their equilibration processes. Comparison of the results obtained with three different catalysts was key to properly attributing the derived characteristic time constants to different ethylene NSIM interconversion processes: ∼3-6 s for interconversion between NSIMs with the same inversion symmetry (i.e., within g or u manifolds) and ∼1700-2200 s between NSIMs with different inversion symmetries (i.e., between g and u manifolds).

Toward Lung Ventilation Imaging Using Hyperpolarized Diethyl Ether Gas Contrast Agent.

Hyperpolarized 129Xe gas was FDA-approved as an inhalable contrast agent for magnetic resonance imaging of a wide range of pulmonary diseases in December 2022. Despite the remarkable success in clinical research settings, the widespread clinical translation of HP 129Xe gas faces two critical challenges: the high cost of the relatively low-throughput hyperpolarization equipment and the lack of 129Xe imaging capability on clinical MRI scanners, which have narrow-bandwidth electronics designed only for proton (1H) imaging. To solve this translational grand challenge of gaseous hyperpolarized MRI contrast agents, here we demonstrate the utility of batch-mode production of proton-hyperpolarized diethyl ether gas via heterogeneous pairwise addition of parahydrogen to ethyl vinyl ether. An approximately 0.1-liter bolus of hyperpolarized diethyl ether gas was produced in 1 second and injected in excised rabbit lungs. Lung ventilation imaging was performed using sub-second 2D MRI with up to 2×2 mm2 in-plane resolution using a clinical 0.35 T MRI scanner without any modifications. This feasibility demonstration paves the way for the use of inhalable diethyl ether as a gaseous contrast agent for pulmonary MRI applications using any clinical MRI scanner.

MATRESHCA: Microtesla Apparatus for Transfer of Resonance Enhancement of Spin Hyperpolarization via Chemical Exchange and Addition.

We present an integrated, open-source device for parahydrogen-based hyperpolarization processes in the microtesla field regime with a cost of components of less than $7000. The device is designed to produce a batch of 13C and 15N 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., 13C and 15N). 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 [1-13C]acetate (P13C = 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 13C and 15N spins in a wide range of biologically relevant molecules, including [1-13C]pyruvate (P13C = 14%, [c] = 27 mM), [1-13C]-α-ketoglutarate (P13C = 17%), [1-13C]ketoisocaproate (P13C = 18%), [15N3]metronidazole (P15N = 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.

Carbon-13 Radiofrequency Amplification by Stimulated Emission of Radiation of the Hyperpolarized Ketone and Hemiketal Forms of Allyl [1-13C]Pyruvate.

13C 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 13C nuclear spins that also need to be synchronized with MRI field gradient pulses. Here, we demonstrate sensing of hyperpolarized allyl [1-13C]pyruvate via the stimulated emission of radiation that mitigates the requirements currently blocking broader adoption. Specifically, 13C Radiofrequency Amplification by Stimulated Emission of Radiation (13C 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 13C polarization of 4%. Moreover, parahydrogen-induced polarization allowed for the preparation of a mixture of ketone and hemiketal forms of hyperpolarized allyl [1-13C]pyruvate, which are separated by 10 ppm in 13C NMR spectra. This is a good model system to study the simultaneous 13C RASER signals of multiple 13C species. This system models the metabolic production of hyperpolarized [1-13C]lactate from hyperpolarized [1-13C]pyruvate, which has a similar chemical shift difference. Our results show that 13C 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, 13C stimulated emission is confined to this species only, therefore enabling the background-free detection of individual hyperpolarized 13C signals. The reported results pave the way to novel sensing approaches of 13C hyperpolarized pyruvate, potentially unlocking hyperpolarized 13C MRI on virtually any MRI system─an attractive vision for the future molecular imaging and diagnostics.

Gladstone-Dale compatibility, electronic polarizability and vibrational spectroscopy of minerals and inorganic compounds with V4+O and V4+O2 vanadyl groups.

VO and VO2 vanadyl groups with short (typically 1.57-1.68 Å), essentially covalent, V-O bonds are common for V4+-bearing oxysalts with [5]- and [6]-coordinated vanadium. There is a clear negative correlation between vanadyl bond lengths and wavenumbers of the bands of V-O stretching vibrations in infrared spectra (in the range 1000-880 cm-1). Optical, structural and chemical data for vanadyl minerals are used to calculate Gladstone-Dale compatibility coefficients. Gladstone-Dale compatibility indices of minerals containing vanadyl bonds are compared with total electronic polarizabilities of V4+. Unlike compounds of [5]-coordinated Ti4+, for most minerals with V4+=O (vanadyl) bonds there is good agreement between measured refractive indices and those calculated based on the polarizability concept.

New data on the crystal chemistry of the natural two-layer aluminosilicates latiumite and tuscanite.

The crystal chemistry of the natural microporous two-layer aluminosilicates (2D zeolites) latiumite and tuscanite is re-investigated based on new data on the chemical composition, crystal structures, and infrared and Raman spectra. The CO32--depleted and P- and H-enriched samples from Sacrofano paleovolcano, Lazio, Italy, are studied. Both minerals are monoclinic; latiumite P21, a = 12.0206 (3), b = 5.09502 (10), c = 10.8527 (3) Å, ß = 107.010 (3)°, V = 635.60 (3) Å3 and tuscanite P21/a, a = 23.9846 (9), b = 5.09694 (15), c = 10.8504 (4) Å, ß = 107.032 (4)°, V = 1268.26 (8) Å3. The obtained crystal chemical formulae (Z = 2 for both minerals) are [(H3O)0.48(H2O)0.24K0.28](Ca2.48K0.21Na0.21Sr0.06Mg0.04)(Si2.86Al2.14O11)[(SO4)0.70(PO4)0.20](CO3)0.10 for latiumite and [(H3O)0.96(H2O)0.58K0.46](Ca4.94K0.44Na0.45Sr0.09Mg0.08)(Si5.80Al4.20O22)[(SO4)1.53(PO4)0.33](CO3)0.14 for tuscanite. These minerals are dimorphous. Both latiumite and tuscanite show distinct affinity for the PO43- anion. Hydrolytic alteration of these minerals results in partial leaching of potassium accompanied by protonation and hydration which is an important precondition for the existence of ion/proton conductivity of related materials.

Crystal Chemistry of the Copper Oxalate Biomineral Moolooite: The First Single-Crystal X-ray Diffraction Studies and Thermal Behavior.

Moolooite, Cu(C2O4)·nH2O, is a typical biomineral which forms due to Cu-bearing minerals coming into contact with oxalic acid sources such as bird guano deposits or lichens, and no single crystals of moolooite of either natural or synthetic origin have been found yet. This paper reports, for the first time, on the preparation of single crystals of a synthetic analog of the copper-oxalate biomineral moolooite, and on the refinement of its crystal structure from the single-crystal X-ray diffraction (SCXRD) data. Along with the structural model, the SCXRD experiment showed the significant contribution of diffuse scattering to the overall diffraction data, which comes from the nanostructural disorder caused by stacking faults of Cu oxalate chains as they lengthen. This type of disorder should result in the chains breaking, at which point the H2O molecules may be arranged. The amount of water in the studied samples did not exceed 0.15 H2O molecules per formula unit. Apparently, the mechanism of incorporation of H2O molecules governs the absence of good-quality single crystals in nature and a lack of them in synthetic experiments: the more H2O content in the structure, the stronger the disorder will be. A description of the crystal structure indicates that the ideal structure of the Cu oxalate biomineral moolooite should not contain H2O molecules and should be described by the Cu(C2O4) formula. However, it was shown that natural and synthetic moolooite crystals contain a significant portion of "structural" water, which cannot be ignored. Considering the substantially variable amount of water, which can be incorporated into the crystal structure, the formula Cu(C2O4)·nH2O for moolooite is justified.

Refinement of the crystal structure of fresnoite, Ba2TiSi2O8, from Löhley (Eifel district, Germany); Gladstone-Dale compatibility, electronic polarizability and vibrational spectroscopy of minerals and inorganic compounds with pentacoordinated TiIV and a titanyl bond.

Most known compounds with five-coordinated Ti4+ are natural and synthetic titanosilicates. The crystal structure of natural fresnoite, Ba2TiSi2O8 [tetragonal, space group P4bm, a = 8.510 (1) Å, c = 5.197 (1) Å, V = 376.4 (1) Å3, Z = 2], has been refined to R = 0.011 on the basis of 807 unique single-crystal reflections with I > 2σ(I). Titanium has fivefold coordination with one short (`titanyl') bond of 1.692 (5) Å. Bonds in the TiO5 polyhedron are discussed in comparison to analogous coordination polyhedra in other minerals and compounds. A review of all known compounds with Ti4+O5 polyhedra shows that most of them are titanosilicates in which titanium forms a short Ti-O bond (∼1.61 to ∼1.77 Å). Poor Gladstone-Dale compatibility between chemical composition, optical characteristics and density of these compounds is explained by the anomalous contribution of [5]Ti4+ to the optical properties as shown by calculations based on the relationship between electronic polarizabilities and refractive indices. An improved Gladstone-Dale coefficient of 0.29 is suggested for TiO2 with [5]Ti4+. A negative correlation between `titanyl' bond lengths and wavenumbers of the bands of Ti-O stretching vibrations (in the range of 890-830 cm-1) in infrared and Raman spectra is observed.

Infrared spectroscopy as a tool for the analysis of framework topology and extra-framework components in microporous cancrinite- and sodalite-related aluminosilicates.

The identification of the framework type in multilayer cancrinite- and sodalite-group minerals and synthetic compounds is predominantly based on the unit-cell dimensions determined from powder or single-crystal X-ray diffraction data, by analogy with previously characterized samples with known crystal structures. However, topological type of the framework cannot be reliably determined in this way because of the different possible ABC staking sequences and different sets of cages with the same number of layers in the repeat unit. To solve this problem, additional criteria are required. The use of infrared (IR) spectroscopy makes it possible to distinguish topologically different types with the same unit-cell parameters. The most important diagnostic range in the IR spectrum (the "finger-print region", from 510 to 760 cm-1) corresponds to the O-T-O bending vibrations (T = Si, Al). The spectral bands at 705 ± 8, 528 ± 5, 547 ± 4, and 555 ± 3 cm-1 indicate the presence of the sodalite, Losod, liottite, and giuseppettite cages, respectively. The band at 528 ± 5 cm-1 shifts towards ∼518 cm-1 in the case when Losod cage hosts carbonate group. The IR spectrum in the "finger-print region" can be also used to identify a mineral species belonging to two-layer or three-layer minerals with different extra-framework compositions. The wavenumber of the antisymmetric stretching mode of the 12CO2 molecule, which is a common admixed extra-framework constituent in minerals belonging to the cancrinite and sodalite groups, depends on the kind of the host cage or channel: 2340-2343 cm-1 for the sodalite cage, 2338 cm-1 for the Losod cage, and 2351-2353 cm-1 for the liottite cage and wide channel in the cancrinite-type framework.

Subsecond Three-Dimensional Nitrogen-15 Magnetic Resonance Imaging Facilitated by Parahydrogen-Based Hyperpolarization.

Magnetic resonance imaging (MRI) provides unique information about the internal structure and function of living organisms in a non-invasive way. The use of conventional proton MRI for the observation of real-time metabolism is hampered by the dominant signals of water and fat, which are abundant in living organisms. Heteronuclear MRI in conjunction with the hyperpolarization methods does not encounter this issue. In this work, we polarized 15N nuclei of [15N1]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 15N MRI of the hyperpolarized 15N-labeled drug was acquired in 0.1 s with a signal-to-noise ratio of 70. In addition, the NMR signal enhancements for 15N-enriched fampridine and fampridine with a natural abundance of 15N nuclei were compared and an explanation for their difference was proposed.

The role of local heteropolyhedral substitutions in the stoichiometry, topological characteristics and ion-migration paths in the eudialyte-related structures: a quantitative analysis.

Topological analysis of the heteropolyhedral MT framework (where M and T are octahedral and tetrahedral cations, respectively) in the eudialyte-type structure and its derivatives was performed based on a natural tiling analysis of the 3D cation. To analyze the migration paths of sodium cations in these structures, the Voronoi method was used. The parental eudialyte-type MT framework is formed by isolated ZO6 octahedra, six-membered [M(1)6O24] rings of edge-sharing M(1)O6 octahedra, and two kinds of rings of tetrahedra, [Si3O9] and [Si9O27]. Different occupancies of M(2), M(3) and M(4) sites with variable coordination numbers by the additional Q, T* and M* cations, respectively, result in 12 different types of the MT framework. Based on the results of natural tilings calculations as well as theoretical analysis of migration paths, it is found that Na+ ions can migrate through six- and seven-membered rings, while all other rings are too small for the migration. In eight types of MT frameworks, Na+-ion migration and diffusion is possible at ambient temperature and pressure, while in four other types cages are connected by narrow windows and, as a result, the Na+ diffusion in them is complicated at ambient conditions because of the window diameter, but may be possible either at higher temperatures or under mild geological conditions for long periods of time.

Crystal chemistry of lamprophyllite-group minerals from the Murun alkaline complex (Russia) and pegmatites of Rocky Boy and Gordon Butte (USA): single crystal X-ray diffraction and Raman spectroscopy study.

Specific features of the crystal chemistry of lamprophyllite-group minerals (LGMs) are discussed using the available literature data and the results of the single-crystal X-ray diffraction and a Raman spectroscopic studies of several samples taken from the Murun alkaline complex (Russia), and Rocky Boy and Gordon Butte pegmatites (USA) presented here. The studied samples are unique in their chemical features and the distribution of cations over structural sites. In particular, the sample from the Gordon Butte pegmatite is a member of the barytolamprophyllite-emmerichite solid solution series, whereas the samples from the Murun alkaline complex and from the Rocky Boy pegmatite are intermediate members of the solid solution series formed by lamprophyllite and a hypothetical Sr analogue of emmerichite. The predominance of O2- over OH- and F- at the X site is a specific feature of sample Cha-192 from the Murun alkaline complex. New data on the Raman spectra of LGMs obtained in this work show that the wavenumbers of the O-H stretching vibrations depend on the occupancies of the M2 and M3 sites coordinating with (OH)- groups. Cations other than Na+ and Ti4+ (mainly, Mg and Fe3+) can play a significant role in the coordination of the X site occupied by (OH)-. Data on polarized Raman spectra of an oriented sample indicate that the OH groups having different local coordinations have similar orientations with respect to the crystal. The calculated measures of similarity (Δ) for lamprophyllite and ericssonite are identical (0.157 and 0.077 for the 2M- and 2O-polytypes, respectively), which indicates that these minerals are crystal-chemically isotypic and probably should be considered within the same mineral group by analogy to the other mineralogical groups which combine isotypic minerals.

Synthetic Approaches for 15 N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for 15 N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields.

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by 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 the 13 C and 15 N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their long T1 allows hyperpolarized states to be retained 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 the hyperpolarization of 15 N nuclei. Although large sensitivity gains are enabled by hyperpolarization, 15 N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of 15 N-labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through 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.

Heterogeneous 1 H and 13 C Parahydrogen-Induced Polarization of Acetate and Pyruvate Esters.

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. Herein, 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/TiO2 catalysts in methanol-d4 and in D2 O. The maximum obtained 1 H polarization was 0.6±0.2 % (for propyl acetate in CD3 OD), while the highest 13 C polarization was 0.10±0.03 % (for ethyl acetate in CD3 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.

PHIP hyperpolarized [1-13C]pyruvate and [1-13C]acetate esters via PH-INEPT polarization transfer monitored by 13C NMR and MRI.

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.

Synthesis and 15 N NMR Signal Amplification by Reversible Exchange of [15 N]Dalfampridine at Microtesla Magnetic Fields.

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.

Heterogeneous Parahydrogen-Induced Polarization of Diethyl Ether for Magnetic Resonance 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/TiO2 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 mm2 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 NMR Hyperpolarization of Radiosensitizing Antibiotic Nimorazole by Reversible Parahydrogen Exchange in Microtesla Magnetic Fields.

Nimorazole belongs to the imidazole-based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15 N3 ]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next-generation MRI-LINAC systems. Herein, we report the first steps to create long-lasting (for tens of minutes) hyperpolarized state on three 15 N sites of [15 N3 ]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000-fold at 1.4 T (corresponding to P15N of 3.2 %) by 15 N-15 N spin-relayed SABRE-SHEATH hyperpolarization technique, relying on simultaneous exchange of [15 N3 ]nimorazole and parahydrogen on polarization transfer Ir-IMes catalyst. The presented results pave the way to efficient spin-relayed SABRE-SHEATH hyperpolarization of a wide range of imidazole-based antibiotics and chemotherapeutics.

Low-Flammable Parahydrogen-Polarized MRI Contrast Agents.

Many MRI contrast agents formed with the parahydrogen-induced polarization (PHIP) technique exhibit biocompatible profiles. In the context of respiratory imaging with inhalable molecular contrast agents, the development of nonflammable contrast agents would nonetheless be highly beneficial for the biomedical translation of this sensitive, high-throughput and affordable hyperpolarization technique. To this end, we assess the hydrogenation kinetics, the polarization levels and the lifetimes of PHIP hyperpolarized products (acids, ethers and esters) at various degrees of fluorine substitution. The results highlight important trends as a function of molecular structure that are instrumental for the design of new, safe contrast agents for in vivo imaging applications of the PHIP technique, with an emphasis on the highly volatile group of ethers used as inhalable anesthetics.