Category Archives: SABRE

SABRE: Chemical kinetics and spin dynamics of the formation of hyperpolarization

Barskiy, Danila A., Stephan Knecht, Alexandra V. Yurkovskaya, and Konstantin L. Ivanov. “SABRE: Chemical Kinetics and Spin Dynamics of the Formation of Hyperpolarization.” Progress in Nuclear Magnetic Resonance Spectroscopy 114–115 (October 2019): 33–70.

https://doi.org/10.1016/j.pnmrs.2019.05.005

In this review, we present the physical principles of the SABRE (Signal Amplification By Reversible Exchange) method. SABRE is a promising hyperpolarization technique that enhances NMR signals by transferring spin order from parahydrogen (an isomer of the H2 molecule that is in a singlet nuclear spin state) to a substrate that is to be polarized. Spin order transfer takes place in a transient organometallic complex which binds both parahydrogen and substrate molecules; after dissociation of the SABRE complex, free hyperpolarized substrate molecules are accumulated in solution. An advantage of this method is that the substrate is not modified chemically, and its polarization can be regenerated multiple times by bubbling fresh parahydrogen through the solution. Thus, SABRE requires two key ingredients: (i) polarization transfer and (ii) chemical exchange of both parahydrogen and substrate. While there are several excellent reviews on applications of SABRE, the background of the method is discussed less frequently. In this review we aim to explain in detail how SABRE hyperpolarization is formed, focusing on key aspects of both spin dynamics and chemical kinetics, as well as on the interplay between them. Hence, we first cover the known spin order transfer methods applicable to SABRE — cross-relaxation, coherent spin mixing at avoided level crossings, and coherence transfer — and discuss their practical implementation for obtaining SABRE polarization in the most efficient way. Second, we introduce and explain the principle of SABRE hyperpolarization techniques that operate at ultralow (<1 lT), at low (1lT to 0.1 T) and at high (>0.1 T) magnetic fields. Finally, chemical aspects of SABRE are discussed in detail, including chemical systems that are amenable to SABRE and the exchange processes that are required for polarization formation. A theoretical treatment of the spin dynamics and their interplay with chemical kinetics is also presented. This review outlines known aspects of SABRE and provides guidelines for the design of new SABRE experiments, with the goal of solving practical problems of enhancing weak NMR signals.

The application of novel Ir-NHC polarization transfer complexes by SABRE #DNPNMR #SABRE

Hadjiali, Sara, Marvin Bergmann, Alexey Kiryutin, Stephan Knecht, Grit Sauer, Markus Plaumann, Hans-Heinrich Limbach, Herbert Plenio, and Gerd Buntkowsky. “The Application of Novel Ir-NHC Polarization Transfer Complexes by SABRE.” The Journal of Chemical Physics 151, no. 24 (December 28, 2019): 244201.

https://doi.org/10.1063/1.5128091

In recent years, the hyperpolarization method Signal Amplification By Reversible Exchange (SABRE) has developed into a powerful technique to enhance Nuclear Magnetic Resonance (NMR) signals of organic substrates in solution (mostly via binding to the nitrogen lone pair of N-heterocyclic compounds) by several orders of magnitude. In order to establish the application and development of SABRE as a hyperpolarization method for medical imaging, the separation of the Ir-N-Heterocyclic Carbene (Ir-NHC) complex, which facilitates the hyperpolarization of the substrates in solution, is indispensable. Here, we report for the first time the use of novel Ir-NHC complexes with a polymer unit substitution in the backbone of N-Heterocyclic Carbenes (NHC) for SABRE hyperpolarization, which permits the removal of the complexes from solution after the hyperpolarization of a target substrate has been generated.

Hyperpolarising Pyruvate through Signal Amplification by Reversible Exchange (SABRE)

Iali, Wissam, Soumya S. Roy, Ben J. Tickner, Fadi Ahwal, Aneurin J. Kennerley, and Simon B. Duckett. “Hyperpolarising Pyruvate through Signal Amplification by Reversible Exchange (SABRE).” Angewandte Chemie 131, no. 30 (July 22, 2019): 10377–81.

https://doi.org/10.1002/ange.201905483.

Hyperpolarisation methods that premagnetise agents such as pyruvate are currently receiving significant attention because they produce sensitivity gains that allow disease tracking and interrogation of cellular metabolism by magnetic resonance. Here, we communicate how signal amplification by reversible exchange (SABRE) can provide strong 13C pyruvate signal enhancements in seconds through the formation of the novel polarisation transfer catalyst [Ir(H)2(h2-pyruvate)(DMSO)(IMes)]. By harnessing SABRE, strong signals for [1-13C]- and [2-13C]pyruvate in addition to a long-lived singlet state in the [1,2-13C2] form are readily created; the latter can be observed five minutes after the initial hyperpolarisation step. We also demonstrate how this development may help with future studies of chemical reactivity.

“Direct” 13C Hyperpolarization of 13C‐Acetate by MicroTesla NMR Signal Amplification by Reversible Exchange (SABRE)

Gemeinhardt, Max E., Miranda N. Limbach, Thomas R. Gebhardt, Clark W. Eriksson, Shannon L. Eriksson, Jacob R. Lindale, Elysia A. Goodson, Warren S. Warren, Eduard Y. Chekmenev, and Boyd M. Goodson. “‘Direct’ 13C Hyperpolarization of 13C‐Acetate by MicroTesla NMR Signal Amplification by Reversible Exchange (SABRE).” Angewandte Chemie 132, no. 1 (January 2, 2020): 426–31.

https://doi.org/10.1002/ange.201910506

Herein, we demonstrate “direct” hyperpolarization of 13Cacetate via signal amplification by reversible exchange (SABRE). The standard SABRE homogeneous catalyst [“Ir-IMes”; [IrCl(COD)(IMes)], (IMes = 1,3-bis(2,4,6-trimethylphenyl), imidazole-2-ylidene; COD = cyclooctadiene)] was first activated in the presence of an auxiliary substrate (pyridine) in alcohol. Following addition of sodium 1-13Cacetate, parahydrogen bubbling within a microtesla magnetic field (i.e. under conditions of SABRE in SHield Enables Alignment Transfer to Heteronuclei, SABRE-SHEATH) resulted in positive enhancements of up to ~100-fold in the 13C NMR signal compared to thermal equilibrium at 9.4 T. The present results are consistent with a mechanism of “direct” transfer of spin order from parahydrogen to 13C spins of acetate weakly bound to the catalyst, under conditions of fast exchange with respect to the 13C acetate resonance, but we find that relaxation dynamics at microtesla fields alter the optimal matching from the traditional SABRE-SHEATH picture. Further development of this approach could lead to new ways to rapidly, cheaply, and simply hyperpolarize a broad range of substrates (e.g. metabolites with carboxyl groups) for various applications, including biomedical NMR and MRI of cellular and in vivo metabolism.

Reaction Monitoring Using SABRE-Hyperpolarized Benchtop (1 T) NMR Spectroscopy

Semenova, Olga, Peter M. Richardson, Andrew J. Parrott, Alison Nordon, Meghan E. Halse, and Simon B. Duckett. “Reaction Monitoring Using SABRE-Hyperpolarized Benchtop (1 T) NMR Spectroscopy.” Analytical Chemistry, May 2, 2019, acs.analchem.9b00729.

https://doi.org/10.1021/acs.analchem.9b00729

The conversion of [IrCl(COD)(IMes)] (COD = cis,cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of p-H2 and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the parahydrogen (p-H2) based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of singleshot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange reaction (HIE) which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol-d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable, that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which is harnessed here to separate the effects of catalyst formation and substrate deuteration. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data.

Decoupled LIGHT-SABRE variants allow hyperpolarization of asymmetric SABRE systems at an arbitrary field

Lindale, Jacob R., Christian P.N. Tanner, Shannon L. Eriksson, and Warren S. Warren. “Decoupled LIGHT-SABRE Variants Allow Hyperpolarization of Asymmetric SABRE Systems at an Arbitrary Field.” Journal of Magnetic Resonance 307 (October 2019): 106577.

https://doi.org/10.1016/j.jmr.2019.106577

Signal Amplification By Reversible Exchange, or SABRE, uses the singlet-order of parahydrogen to generate hyperpolarized signals on target nuclei, bypassing the limitations of traditional magnetic resonance. Experiments performed directly in the magnet provide a route to generate large magnetizations continuously without having to field-cycle the sample. For heteronuclear SABRE, these high-field methods have been restricted to the few SABRE complexes that exhibit efficient exchange with symmetric ligand environments as co-ligands induce chemical shift differences between the parahydrogen-derived hydrides, destroying the hyperpolarized spin order. Through careful consideration of the underlying spin physics, we introduce 1H decoupled LIGHT-SABRE pulse sequence variants which bypasses this limitation, drastically expanding the scope of heteronuclear SABRE at high field.

High-throughput continuous-flow system for SABRE hyperpolarization

Štěpánek, Petr, Clara Sanchez-Perez, Ville-Veikko Telkki, Vladimir V. Zhivonitko, and Anu M. Kantola. “High-Throughput Continuous-Flow System for SABRE Hyperpolarization.” Journal of Magnetic Resonance 300 (March 2019): 8–17.

https://doi.org/10.1016/j.jmr.2019.01.003

Signal Amplification By Reversible Exchange (SABRE) is a versatile method for hyperpolarizing small organic molecules that helps to overcome the inherent low signal-to-noise ratio of nuclear magnetic resonance (NMR) measurements. It offers orders of magnitude enhanced signal strength, but the obtained nuclear polarization usually rapidly relaxes, requiring a quick transport of the sample to the spectrometer. Here we report a new design of a polarizing system, which can be used to prepare a continuous flow of SABREhyperpolarized sample with a considerable throughput of several mililiters per second and a rapid delivery into an NMR instrument. The polarizer performance under different conditions such as flow rate of the hydrogen or liquid sample is tested by measuring a series of NMR spectra and magnetic resonance images (MRI) of hyperpolarized pyridine in methanol. Results show a capability to continuously produce sample with dramatically enhanced signal over two orders of magnitude. The constant supply of hyperpolarized sample can be exploited, e.g., in experiments requiring multiple repetitions, such as 2D and 3D-NMR or MRI measurements, and also naturally allows measurements of flow maps, including systems with high flow rates, for which the level of achievable thermal polarization might not be usable any more. In addition, the experiments can be viably carried out in a non-deuterated solvent, due to the effective suppression of the thermal polarization by the fast sample flow. The presented system opens the possibilities for SABRE experiments requiring a long-term, stable and high level of nuclear polarization.

Substituent Influences on the NMR Signal Amplification of Ir Complexes with Heterocyclic Carbene Ligands

Hadjiali, Sara, Roman Savka, Markus Plaumann, Ute Bommerich, Sarah Bothe, Torsten Gutmann, Tomasz Ratajczyk, et al. “Substituent Influences on the NMR Signal Amplification of Ir Complexes with Heterocyclic Carbene Ligands.” Applied Magnetic Resonance 50, no. 7 (July 2019): 895–902.

https://doi.org/10.1007/s00723-019-01115-x.

A number of Ir–N-heterocyclic carbene (Ir–NHC) complexes with asymmetric N-heterocyclic carbene (NHC) ligands have been prepared and examined for signal amplification by reversible exchange (SABRE). Pyridine was chosen as model compound for hyperpolarization experiments. This substrate was examined in a solvent mixture using several Ir–NHC complexes, which differ in their NHC ligands. The SABRE polarization was created at 6 mT and the 1H nuclear magnetic resonance signals were detected at 7 T. We show that asymmetric NHC ligands, because of their favorable chemistry, can adapt the SABRE active complexes to different chemical scenarios.

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

Kiryutin, Alexey S., Grit Sauer, Daniel Tietze, Martin Brodrecht, Stephan Knecht, Alexandra V. Yurkovskaya, Konstantin L. Ivanov, Olga Avrutina, Harald Kolmar, and Gerd Buntkowsky. “Ultrafast Single‐Scan 2D NMR Spectroscopic Detection of a PHIP‐Hyperpolarized Protease Inhibitor.” Chemistry – A European Journal 25, no. 16 (March 15, 2019): 4025–30.

https://doi.org/10.1002/chem.201900079

Two-dimensional (2D) NMR is one of the most important spectroscopic tools for the investigation of biological macromolecules. However, owing to the low sensitivity of NMR it takes usually from several minutes to many hours to record such a spectrum. Here we show that a bioactive derivative of the sunflower trypsin inhibitor-1 (SFTI-1), a tetradecapeptide, can be detected by the combination of parahydrogen-induced polarization (PHIP) and ultrafast 2D-NMR spectroscopy (in the following abbreviated as 2D-NMR). The PHIP activity of the inhibitor was achieved by labeling with O-propargyl-Ltyrosine. In 1D-PHIP experiments an enhancement of approximately 1200 compared to normal NMR was found. This enhancement permits measurement of 2D-NMR correlation spectra of low concentrated SFTI-1 in less than 10 seconds, employing ultrafast single-scan 2D-NMR detection. As experimental examples PHIP assisted ultrafast single-scan TOCSY spectra of SFTI-1 are shown.

Quantification of hyperpolarisation efficiency in SABRE and SABRE-Relay enhanced NMR spectroscopy #SABRE #DNP

Richardson, Peter M., Richard O. John, Andrew J. Parrott, Peter J. Rayner, Wissam Iali, Alison Nordon, Meghan E. Halse, and Simon B. Duckett. “Quantification of Hyperpolarisation Efficiency in SABRE and SABRE-Relay Enhanced NMR Spectroscopy.” Physical Chemistry Chemical Physics 20, no. 41 (2018): 26362–71.

https://doi.org/10.1039/C8CP05473H

para-Hydrogen (p-H2) induced polarisation (PHIP) is an increasingly popular method for sensitivity enhancement in NMR spectroscopy. Its growing popularity is due in part to the introduction of the signal amplification by reversible exchange (SABRE) method that generates renewable hyperpolarisation in target analytes in seconds. A key benefit of PHIP and SABRE is that p-H2 can be relatively easily and cheaply produced, with costs increasing with the desired level of p-H2 purity. In this work, the efficiency of the SABRE polarisation transfer is explored by measuring the level of analyte hyperpolarisation as a function of the level of p-H2 enrichment. A linear relationship was found between p-H2 enrichment and analyte 1H hyperpolarisation for a range of molecules, polarisation transfer catalysts, NMR detection fields and for both the SABRE and SABRE-Relay transfer mechanisms over the range 29–99% p-H2 purity. The gradient of these linear relationships were related to a simple theoretical model to define an overall efficiency parameter, E, that quantifies the net fraction of the available p-H2 polarisation that is transferred to the target analyte. We find that the efficiency of SABRE is independent of the NMR detection field and exceeds E = 20% for methyl-4,6-d2-nicotinate when using a previously optimised catalyst system. For the SABRE-Relay transfer mechanism, efficiencies of up to E = 1% were found for 1H polarisation of 1-propanol, when ammonia was used as the polarisation carrier.

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