Alexandra V. Yurkovskaya

Level Anti-Crossings are a Key Factor for Understanding para-Hydrogen-Induced Hyperpolarization in SABRE Experiments

Various hyperpolarization methods are able to enhance the sensitivity of nuclear magnetic resonance (NMR) spectroscopy and magnetic resonance imaging (MRI) by several orders of magnitude. Among these methods are para-hydrogen-induced polarization (PHIP) and signal amplification by reversible exchange (SABRE), which exploit the strong nuclear alignment of para-hydrogen. Several SABRE experiments have been reported but, so far, it has not been possible to account for the experimentally observed sign and magnetic-field dependence of substrate polarization. Herein, we present an analysis based on level anti-crossings (LACs), which provides a complete understanding of the SABRE effect. The field-dependence of both net and anti-phase polarization is measured for several ligands, which can be reproduced by the theory. The similar SABRE field-dependence for different ligands is also explained. In general, the LAC concept allows complex spin dynamics to be unraveled, and is crucial for optimizing the performance of novel hyperpolarization methods in NMR and MRI techniques.

RF-SABRE: A Way to Continuous Spin Hyperpolarization at High Magnetic Fields

A new technique is developed that allows one to carry out the signal amplification by reversible exchange (SABRE) experiments at high magnetic field. SABRE is a hyperpolarization method, which utilizes transfer of spin order from para-hydrogen to the spins of a substrate in transient iridium complexes. Previously, it has been thought that such a transfer of spin order is only efficient at low magnetic fields, notably, at level anti-crossing (LAC) regions. Here it is demonstrated that LAC conditions can also be fulfilled at high fields under the action of a RF field. The high-field RF-SABRE experiment can be implemented using commercially available nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) machines and does not require technically demanding field-cycling. The achievable NMR enhancements are around 100 for several substrates as compared to their NMR signals at thermal equilibrium conditions at 4.7 T. The frequency dependence of RF-SABRE is comprised of well pronounced peaks and dips, whose position and amplitude are conditioned solely by the magnetic resonance parameters such as chemical shifts and scalar coupling of the spin system involved in the polarization transfer and by the amplitude of the RF field. Thus, the proposed method can serve as a new sensitive tool for probing transient complexes. Simulations of the dependence of magnetization transfer (i.e., NMR signal amplifications) on the frequency and amplitude of the RF field are in good agreement with the developed theoretical approach. Furthermore, the method enables continuous re-hyperpolarization of the SABRE substrate over a long period of time, giving a straightforward way to repetitive NMR experiments.

Investigation of the magnetic field dependence of CIDNP in multinuclear radical pairs. 1. Photoreaction of histidine and comparison of model calculation with experimental data

Magnetic field effects on CIDNP formed in the diamagnetic products of geminate recombination of photo-generated radical pairs are calculated at arbitrary field strength. The simulations are based on a model that uses a full quantum mechanical description of the polarized nuclei and a semiclassical account of all other nuclear spins. The results are compared with CIDNP experiments on the photoreaction between N-acetylhistidine and 2,2′-dipyridine in fields between 0 and 7 T employing field cycling between a variable field of polarization and a fixed field of detection. To allow quantitative comparison the simulation takes into account the effects of adiabatic field change and of RF excitation pulse angle on the NMR intensity. Both net and multiplet polarization as observed in two coupled spin pairs (CH2 protons in β position of histidine, and protons in H2,H4 position of its ring) are well reproduced over the whole field range. The wide applicability of the theoretical model and the possibility to extend it to larger spin systems make it particularly useful for the analysis of CIDNP in protein systems.

Transfer of SABRE-derived hyperpolarization to spin-1/2 heteronuclei

In this paper, we describe a method of hyper-polarizing “insensitive” Nuclear Magnetic Resonance (NMR) nuclei by exploiting the SABRE (Signal Amplification By Reversible Exchange) technique and transferring spin order from protons originating from parahydrogen. We demonstrate that hyperpolarization transfer is due to a coherent mechanism, which is operative at (i) very low magnetic field; (ii) geomagnetic field; (iii) high field in the presence of a suitable radiofrequency-excitation scheme. Experiments are performed using 15N-labelled pyridine as the SABRE substrate; NMR enhancements achieved for 15N nuclei are more than 1000 for free pyridine in solution and more than 20 000 for pyridine bound to the SABRE complex. High-field SABRE experiments are particularly important for enhancing the sensitivity of NMR methods: they enable strong signal enhancements and avoid technically demanding field-cycling. Furthermore, such experiments use very low power for NMR excitation and make feasible continuous re-hyperpolarization of the substrate in high-field experiments: polarization can be quickly restored to the maximal level within only 15 seconds with the result that polarization levels stay constant over several hundred experiments. The techniques outlined are applicable to hyper-polarizing spin-1/2 hetero-nuclei, such as 13C, 19F, 31P, etc. Development of such methods opens new avenues in NMR spectroscopy and imaging, which were out of reach for sensitivity reasons.

Creating Long-Lived Spin States at Variable Magnetic Field by Means of Photochemically Induced Dynamic Nuclear Polarization

We have shown that long-lived spin states (LLS) can be selectively populated by photogenerated chemically induced dynamic nuclear polarization (CIDNP) over a wide range of magnetic fields. Relaxation times of LLS of the β-CH2 protons in N-acetyl histidine and partially deuterated histidine have been measured. Our experiments demonstrate that CIDNP enables creating LLS in the amino acid in a field range of up to a few Tesla and that their lifetimes can be 45 times longer than T1. The advantage of the method is thus two-fold: it allows one to accumulate high levels of spin hyperpolarization and to preserve them for periods of time far exceeding T1. Therefore, photo-CIDNP is a technique suitable for creating long-lived spin order in biologically relevant molecules.

Quantitative description of the SABRE process: rigorous consideration of spin dynamics and chemical exchange

A consistent theoretical description of the spin dynamics and chemical kinetics underlying the SABRE (Signal Amplification By Reversible Exchange) process is proposed and validated experimentally. SABRE is a promising method for Nuclear Magnetic Resonance (NMR) signal enhancement, which exploits the transfer of strong non-thermal spin order from parahydrogen (the H2 molecule in its singlet spin state) to a substrate in a transient organometallic complex. A great advantage of the SABRE method is that the substrate acquires strong nuclear spin polarization without being modified chemically, as it is only transiently bound to the complex. However, for the same reason theoretical treatment of SABRE meets difficulties because of the interplay of the spin dynamics with the association–dissociation reactions of the SABRE complex. Here we propose a quantitative model, which takes into account both the spin evolution in the SABRE complex and the substrate exchange between the free and bound forms. The model allows for the calculation of the substrate spin polarization dependency on various parameters, such as the external magnetic field strength and complex association–dissocation rates, and enables the simulation of experimental data for the SABRE time dependence. This investigation opens new insights into the SABRE process and can be generalized to treat more complex cases, such as SABRE facilitated by NMR pulses.

A fast field-cycling device for high-resolution NMR: Design and application to spin relaxation and hyperpolarization experiments

A device for performing fast magnetic field-cycling NMR experiments is described. A key feature of this setup is that it combines fast switching of the external magnetic field and high-resolution NMR detection. The field-cycling method is based on precise mechanical positioning of the NMR probe with the mounted sample in the inhomogeneous fringe field of the spectrometer magnet. The device enables field variation over several decades (from 100μT up to 7T) within less than 0.3s; progress in NMR probe design provides NMR linewidths of about 10(-3)ppm. The experimental method is very versatile and enables site-specific studies of spin relaxation (NMRD, LLSs) and spin hyperpolarization (DNP, CIDNP, and SABRE) at variable magnetic field and at variable temperature. Experimental examples of such studies are demonstrated; advantages of the experimental method are described and existing challenges in the field are outlined.

Spin polarization transfer mechanisms of SABRE: A magnetic field dependent study.

We have investigated the magnetic field dependence of Signal Amplification By Reversible Exchange (SABRE) arising from binding of para-hydrogen (p-H2) and a substrate to a suitable transition metal complex. The magnetic field dependence of the amplification of the (1)H Nuclear Magnetic Resonance (NMR) signals of the released substrates and dihydrogen, and the transient transition metal dihydride species shows characteristic patterns, which is explained using the theory presented here. The generation of SABRE is most efficient at low magnetic fields due to coherent spin mixing at nuclear spin Level Anti-Crossings (LACs) in the SABRE complexes. We studied two Ir-complexes and have shown that the presence of a (31)P atom in the SABRE complex doubles the number of LACs and, consequently, the number of peaks in the SABRE field dependence. Interestingly, the polarization of SABRE substrates is always accompanied by the para-to-ortho conversion in dihydride species that results in enhancement of the NMR signal of free (H2) and catalyst-bound H2 (Ir-HH). The field dependences of hyperpolarized H2 and Ir-HH by means of SABRE are studied here, for the first time, in detail. The field dependences depend on the chemical shifts and coupling constants of Ir-HH, in which the polarization transfer takes place. A negative coupling constant of -7Hz between the two chemically equivalent but magnetically inequivalent hydride nuclei is determined, which indicates that Ir-HH is a dihydride with an HH distance larger than 2Å. Finally, the field dependence of SABRE at high fields as found earlier has been investigated and attributed to polarization transfer to the substrate by cross-relaxation. The present study provides further evidence for the key role of LACs in the formation of SABRE-derived polarization. Understanding the spin dynamics behind the SABRE method opens the way to optimizing its performance and overcoming the main limitation of NMR, its notoriously low sensitivity.

Investigation of the magnetic field dependence of CIDNP in multi-nuclear radical pairs.

The magnetic field dependence of chemically induced dynamic nuclear polarization (CIDNP) formed in the photoreaction of excited 2,2′-dipyridyl and tyrosine is measured in the field range 0–7 T and compared with numerical simulations. The experiments employ field cycling between a variable field of polarization and a fixed field of detection. The simulations of CIDNP are based on the low-viscosity approximation in the Green function theory of geminate reactions. The effects of adiabatic field change and of duration of the RF excitation pulse are taken into account. Good agreement between theory and experiment in the whole field range is found for both net and multiplet polarization as observed in three coupled spin pairs (CH2 protons in β-position of tyrosine, H2,3 and H5,6 protons of its ring). The wide applicability of the theoretical model and the experimental technique make them useful for the characterization of shortlived reaction intermediates and are suited to CIDNP studies of protein surface structure and folding process of protein.

High resolution NMR study of T1 magnetic relaxation dispersion. II. Influence of spin-spin couplings on the longitudinal spin relaxation dispersion in multispin systems

Effects of scalar spin-spin interactions on the nuclear magnetic relaxation dispersion (NMRD) of coupled multispin systems were analyzed. Taking spin systems of increasing complexity we demonstrated pronounced influence of the intramolecular spin-spin couplings on the NMRD of protons. First, at low magnetic fields where there is strong coupling of spins the apparent relaxation times of the coupled spins become equal. Second, there are new features, which appear at the positions of the nuclear spin level anticrossings. Finally, in coupled spin systems there can be a coherent contribution to the relaxation kinetics present at low magnetic fields. All these peculiarities caused by spin-spin interactions are superimposed on the features in NMRD, which are conditioned by changes of the motional regime. Neglecting the effects of couplings may lead to misinterpretation of the NMRD curves and significant errors in determining the correlation times of molecular motion. Experimental results presented are in good agreement with theoretical calculations.