Search

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

In the majority of hydrogenative PHIP (Parahydrogen Induced Polarization) experiments, the hydrogen molecule undergoes pairwise cis-addition to an unsaturated precursor to occupy vicinal positions on the product molecule. However, some ruthenium-based hydrogenation catalysts induce geminal hydrogenation, leading to a reaction product in which the twohydrogen atoms are transferred to the same carbon center, forming a methylene (CH2) group. The singlet order of parahydrogen is substantially retained over the geminal hydrogenation reaction, giving rise to a singlet-hyperpolarized CH2 group. Although the T1 relaxation times of the methylene protons are often short, the singlet order has a long lifetime, providing that singlet-triplet mixing is suppressed, either by chemical equivalence of the protons or by applying a resonant radiofrequency field. The long lifetime of the singlet order enables the accumulation of hyperpolarization during the slow hydrogenation reaction. We introduce a kinetic model for the behaviour of the observed hyperpolarized signals, including both the chemical kinetics and the spin dynamics of the reacting molecules. Our work demonstrates the feasibility of producing singlet-hyperpolarized methylene moieties by parahydrogen-induced polarization. This potentially extends the range of molecular agents which maybe generated in a hyperpolarized state by chemical reactions of parahydrogen.

Parahydrogen is an inexpensive and readily available source of hyperpolarization used to enhance magnetic resonance signals by up to four orders of magnitude above thermal signals obtained at ∼10 T. A significant challenge for applications is fast signal decay after hyperpolarization. Here we use parahydrogen-based polarization transfer catalysis at microtesla fields (first introduced as SABRE-SHEATH) to hyperpolarize 13C2 spin pairs and find decay time constants of 12 s for magnetization at 0.3 mT, which are extended to 2 min at that same field, when long-lived singlet states are hyperpolarized instead. Enhancements over thermal at 8.5 T are between 30 and 170 fold (0.02 to 0.12% polarization). We control the spin dynamics of polarization transfer by choice of microtesla field, allowing for deliberate hyperpolarization of either magnetization or long-lived singlet states. Density functional theory calculations and experimental evidence identify two energetically close mechanisms for polarization transfer...

Nuclear spin hyperpolarization techniques are revolutionizing the field of 13C molecular MRI. While dissolution dynamic nuclear polarization (d-DNP) is currently the leading technique, it is generally slow (requiring ≈1 h) and costly (≈$USD106). As a consequence of carbon's central place in biochemistry, tremendous progress using 13C d-DNP bioimaging has been demonstrated to date including a number of clinical trials. Despite numerous attempts to develop alternatives to d-DNP, the competing methods have faced significant translational challenges. Efficient hyperpolarization of 15N, 31P, and other heteronuclei using signal amplification by reversible exchange (SABRE) has been reported in 2015, but extension of this technique to 13C has proven to be challenging. Here, we present efficient hyperpolarization of 13C nuclei using micro-Tesla SABRE. Up to ca. 6700-fold enhancement of nuclear spin polarization at 8.45 T is achieved within seconds, corresponding to P13C ≈4.4 % using 50 % parahydrogen (P13C >14 % would be feasible using more potent ≈100 % parahydrogen). Importantly, the 13C polarization achieved via SABRE strongly depends not only upon spin–lattice relaxation, but also upon the presence of 15N (I=1/2) versus quadrupolar 14N (I=1) spins in the site binding the hexacoordinate Ir atom of the catalytic complex. We show that different 13C nuclei in the test molecular frameworks—pyridine and acetonitrile—can be hyperpolarized, including 13C sites up to five chemical bonds away from the exchangeable hydrides. The presented approach is highly scalable and can be applied to a rapidly growing number of biomolecules amendable to micro-Tesla SABRE.

A one-pot metal-free conversion of unprotected amino acids to terminal diazirines has been developed using phenyliodonium diacetate (PIDA) and ammonia. This PIDA-mediated transformation occurs

Diazirine moieties are chemically stable and have been incorporated into biomolecules without impediment of biological activity. The

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

Physical chemistry, chemical physics : PCCP 19(33), 21933-21937 (2017). doi:10.1039/C7CP04296E, Published by RSC Publ., Cambridge

NMR with thermal polarization requires relatively concentrated samples, particularly for nuclei with low abundance and low gyromagnetic ratios, such as (15) N. We expand the substrate scope of SABRE, a recently introduced hyperpolarization method, to allow access to (15) N-enriched Schiff bases. These substrates show fractional (15) N polarization levels of up to 2 % while having only minimal (1) H enhancements.

International audience; Diazirine moieties are chemically stable and have been incorporated into biomolecules without impediment of biological activity. The 15N2 labeled diazirines are appealing motifs for hyperpolarization supporting relaxation protected states with long‐lived lifetimes. The (‐CH15N2) diazirine groups investigated here are analogues to methyl groups, which provides the opportunity to transfer polarization stored on a relaxation protected (‐CH15N2) moiety to 1H, thus combining the advantages of long lifetimes of 15N polarization with superior sensitivity of 1H detection. Despite the proximity of 1H to 15N nuclei in the diazirine moiety, 15N T1 times of up to (4.6±0.4) min and singlet lifetimes Ts of up to (17.5±3.8) min are observed. Furthermore, we found terminal diazirines to support hyperpolarized 1H2 singlet states in CH2 groups of chiral molecules. The singlet lifetime of 1H singlets is up to (9.2±1.8) min, thus exceeding 1H T1 relaxation time (at 8.45 T) by a factor of ≈100.

Parahydrogen is an inexpensive and readily available source of hyperpolarization used to enhance magnetic resonance signals by up to 4 orders of magnitude above thermal signals obtained at ~10 T. A significant challenge for applications is fast signal decay after hyperpolarization. Here, we use parahydrogen based polarization transfer catalysis at micro-Tesla fields (first introduced as SABRE-SHEATH) to hyperpolarize 13C2 spin pairs and find decay time constants of 12 s for magnetization at 0.3 mT, which are extended to 2 minutes at that same field, when long-lived singlet states are hyperpolarized instead. Enhancements over thermal at 8.5 T are between 30 and 170 fold (0.02% to 0.12% polarization). We control the spin dynamics of polarization transfer by choice of μT field allowing for deliberate hyperpolarization of either magnetization or long-lived singlet states. Density functional theory (DFT) calculations and experimental evidence identify two energetically close mechanisms for polarization transfer: First, a model that involves direct binding of the 13C2 pair to the polarization transfer catalyst (PTC), and second, a model transferring polarization through auxiliary protons in substrates.

Diazirines are an attractive class of potential molecular tags for magnetic resonance imaging owing to their biocompatibility and ease of incorporation into a large variety of molecules. As recently reported, (15)N(2)-diazirine can be hyperpolarized by the SABRE-SHEATH method, sustaining both singlet and magnetization states, thus offering a path to long-lived polarization storage. Herein, we show the generality of this approach by illustrating that the diazirine tag alone is sufficient for achieving excellent signal enhancements with long-lasting polarization. Our investigations reveal the critical role of Lewis basic additives, including water, on achieving SABRE-promoted hyperpolarization. The application of this strategy to a (15)N(2)-diazirine-containing choline derivative demonstrates the potential of (15)N(2)-diazirines as molecular imaging tags for biomedical applications.

Mobile nuclear magnetic resonance sensors still suffer from relatively high weight and large dimensions, although they are already considerably smaller than superconducting high-field magnets. Application of such sensors for an accurate analysis of rigid materials and thin layers is limited by the echo time of the radiofrequency (rf) coil and the spatial resolution of the sensor. This study presents the construction of a miniaturized NMR-MOUSE® that is reduced to about 90 % in volume and weight compared to a standard Profile NMR-MOUSE®. Thanks to the short dead time of 4 µs of the micro-structured rf coil, short transverse relaxation times of rigid and dry materials can be determined with improved accuracy. Furthermore, it is possible to record depth profiles with high resolution. The large magnetic field gradient of the new set-up leads to enhanced diffusion contrast.

Signal Amplification By Reversible Exchange (SABRE) and its heteronuclear variant SABRE in SHield Enables Alignment Transfer to Heteronuclei create large nuclear magnetization in target ligands, exploiting level crossings in an iridium catalyst that transiently binds both the ligands and parahydrogen. This requires a specific, small magnetic field to match Zeeman splittings to scalar couplings. Here, we explore a different strategy, direct creation of heteronuclear singlet states in the target ligands, which produces enhanced signals at other field strengths, including zero field. We also show that pulsed methods (including pulsed field nulling) coherently and selectively pump such singlets, affording a significant enhancement on the resulting hyperpolarization.

Nuclear magnetic resonance (NMR) spectra of spin systems polarized either thermally or by parahydrogen exhibit strikingly different field dependencies. Thermally polarized spin systems show the well-known roof effect, observed when reducing magnetic field strengths which precludes the independent determination of chemical shift differences and J-coupling constants at low-fields. Quantum mechanical analysis of the NMR spectra with respect to polarization method, pulsed state preparation, and transition probabilities reveals that spectra of parahydrogen polarized systems feature an "inverse roof effect" in the regime where the chemical shift difference δν is smaller than J. This inverse roof effect allows for the extraction of both J-coupling and chemical shift information down to very low fields. Based on a two-spin system, the observed non-linear magnetic field dependence of the splitting of spectral lines is predicted. We develop a general solution for the steady state density matrix of a parahydrogen polarized three-spin system including a heteronucleus which allows explaining experimentally observed (1)H spectra. The analysis of three-spin density matrix illustrates two pathways for an efficient polarization transfer from parahydrogen to (13)C nuclei. Examination of the experimental data facilitates the extraction of all relevant NMR parameters using single-scan, high-resolution (1)H and (13)C NMR spectroscopy at low fields at a fraction of the cost associated with cryogenically cooled high-field NMR spectrometers.

The first instance of para-hydrogen induced polarization (PHIP) in an NMR experiment was serendipitously observed in the 1980s while investigating a hydrogenation reaction (Seldler et al., 1983; Bowers and Weitekamp, 1986, 1987; Eisenschmid et al., 1987) [1] , [2] , [3] , [4] . Remarkably a theoretical investigation of the applicability of para-hydrogen as a hyperpolarization agent was being performed in the 1980’s thereby quickly providing a theoretical basis for the PHIP-effect (Bowers and Weitekamp, 1986) [2] . The discovery of signal amplification by a non-hydrogenating interaction with para-hydrogen has recently extended the interest to exploit the PHIP effect, as it enables investigation of compounds without structural alteration while retaining the advantages of spectroscopy with hyperpolarized compounds [5] . In this article we will place more emphasis of the future applications of the method while only briefly discussing the efforts that have been made in the understanding of the phenomenon and the development of the method so far.

Signal Amplification by Reversible Exchange (SABRE) is a fast and convenient NMR hyperpolarization method that uses cheap and readily available para-hydrogen as a hyperpolarization source. SABRE can hyperpolarize protons and heteronuclei. Here we focus on the heteronuclear variant introduced as SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) and nitrogen-15 targets in particular. We show that 15N-SABRE works more efficiently and on a wider range of substrates than 1H-SABRE, greatly generalizing the SABRE approach. In addition, we show that nitrogen-15 offers significantly extended T1 times of up to 12 minutes. Long T1 times enable higher hyperpolarization levels but also hold the promise of hyperpolarized molecular imaging for several tens of minutes. Detailed characterization and optimization are presented, leading to nitrogen-15 polarization levels in excess of 10% on several compounds.

Welcome to the guest zone: By combining hyperpolarized xenon and simple low-field NMR devices it is possible to obtain more control over hydrogels that show potential as drug delivery systems. An alternative way of polymer swelling-degree determination is demonstrated with real-time NMR analysis. An ideal region for solvent uptake can be defined in which the absorbed solvent molecules are completely confined in the nano-porous network of the hydrogel.

In this article we report the longitudinal relaxation times (T(1)) of various (6)Li salts ((6)LiI, (6)LiCl and (6)LiNO(3)) in D(2)O and H(2)O, measured in low magnetic fields (B(0)=3.5mT). This investigation serves the purpose of clarifying the relaxation behavior of different (6)Li solutions and different concentrations. The measurement were undertaken to establish a framework for future applications of hyperpolarized (6)Li in medical imaging, biological studies and investigations of lithium ion batteries. Time will pass during the transport of hyperpolarized lithium ions to the sample, which leads to a polarization loss. In order to store polarization as long as possible, it is necessary to examine which (6)Li salt solution has the longest relaxation time T(1). Longitudinal relaxation times of (6)Li salts in D(2)O and H(2)O were investigated as a function of concentration and the most extended T(1) was found for (6)LiI in D(2)O and H(2)O. In agreement with the theory the relaxation time T(1) of all (6)Li salts increase with decreasing concentration. In the case of (6)LiI in H(2)O an inverse behavior was observed. We assume that the prolonged T(1) times occur due to formation of (6)LiOH upon the solution of (6)LiI in H(2)O, which settles as a precipitate. By diluting the solution, the precipitate continuously dissolves and approaches T(1) of (6)LiOH (T(1)∼28s), leading to a shorter T(1) relaxation time.

The first instance of para-hydrogen induced polarization (PHIP) in an NMR experiment was serendipitously observed in the 1980s while investigating a hydrogenation reaction (Seldler et al., 1983; Bowers and Weitekamp, 1986, 1987; Eisenschmid et al., 1987) [1] , [2] , [3] , [4] . Remarkably a theoretical investigation of the applicability of para-hydrogen as a hyperpolarization agent was being performed in the 1980’s thereby quickly providing a theoretical basis for the PHIP-effect (Bowers and Weitekamp, 1986) [2] . The discovery of signal amplification by a non-hydrogenating interaction with para-hydrogen has recently extended the interest to exploit the PHIP effect, as it enables investigation of compounds without structural alteration while retaining the advantages of spectroscopy with hyperpolarized compounds [5] . In this article we will place more emphasis of the future applications of the method while only briefly discussing the efforts that have been made in the understanding of the phenomenon and the development of the method so far.

(Received 11 September 2012; revised manuscript received 18 January 2013; published 26 March 2013) We report new phenomena in low-field 1 H nuclear magnetic resonance (NMR) spectroscopy using parahydrogen induced polarization (PHIP), enabling determination of chemical shift differences, �� , and the scalar coupling constant J. NMR experiments performed with thermal polarization in millitesla magnetic fields do not allow the determination of scalar coupling constants for homonuclear coupled spins in the inverse weak coupling regime (�� < J ). We show here that low-field PHIP experiments in the inverse weak coupling regime enable the precise determination of �� and J. Furthermore we experimentally prove that observed splittings are related to �� in a nonlinear way. Naturally abundant 13 C and 29 Si isotopes lead to heteronuclear J-coupled 1 H-multiplet lines with amplitudes significantly enhanced compared to the amplitudes for thermally prepolarized spins. PHIP-enhanced NMR in the millitesla regime allows us to measure characteristic NMR parameters in a single scan using samples containing rare spins in natural abundance. The established approach to liquid-state NMR spectroscopy in high fields is based on resolving NMR lines probing chemical shifts, J-coupling constants, and multiplicity. Those parameters are easily extracted from the spectra, because high-field experiments are typically performed in the weak coupling regime, where �� � J is valid. The clearly separated spectral lines allow identification of molecular structure. In the presence of rare spins additional heteronuclear J-coupled multiplets arise [1,2]. In the last decades various hyperpolarization technologies [3–6] and sensitive detection schemes [7–10 ]h ave rekindled the interest in low-field NMR. High resolution NMR spectroscopy with hyperpolarized molecules has been demonstrated in the Earth’s magnetic field and close to zero field [10–13]. PHIP, where singlet state order (parahydrogen) is transferred into large observable nuclear polarization, offers an attractive means of hyperpolarization [14–18]. NMR spectroscopy with hyperpolarized J-coupled spins at zero and close to zero field [19–21] has been demonstrated. In these cases the presence of rare spins (e.g., 15 N) in the molecule is required to yield observable transitions in J-coupled spin systems. Close to zero field there are still ambiguity problems for molecules with more than two chemical groups and the chemical shift information is lost [22]. The drawbacks of low-field NMR spectroscopy for pure 1 H spin-systems with thermal polarization are the low signal-to-noise ratio (SNR) and the loss of J-coupling and chemical shift information.

Signal Amplification by Reversible-Exchange (SABRE) is a method of hyperpolarizing substrates by polarization transfer from para-hydrogen without hydrogenation. Here, we demonstrate that this method can be applied to hyperpolarize small amounts of all proteinogenic amino acids and some chosen peptides down to the nanomole regime and can be detected in a single scan in low-magnetic fields down to 0.25 mT (10 kHz proton frequency). An outstanding feature is that depending on the chemical state of the used catalyst and the investigated amino acid or peptide, hyperpolarized hydrogen-deuterium gas is formed, which was detected with (1)H and (2)H NMR spectroscopy at low magnetic fields of B(0) = 3.9 mT (166 kHz proton frequency) and 3.2 mT (20 kHz deuterium frequency).

Advances with para-hydrogen induced polarization open up new fields of applications for portable low-field NMR. Here we report the possibility of tracing drugs down to the micromolar regime. We could selectively polarize nicotine quantities similar to those found in one cigarette. Also less than 1 mg of harmine, a drug used for treatment of Parkinson's disease, and morphine extracted from an opium solution were detectable after polarization with para-hydrogen in single-scan (1)H-experiments. Moreover, we demonstrate the possibility to selectively enhance and detect the (1)H-signal of drug molecules with PHIP in proton rich standard solutions that would otherwise mask the (1)H NMR signal of the drug.