Gabriele Stevanato

A nuclear singlet lifetime of more than one hour in room-temperature solution

Nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) are supremely important techniques with numerous applications in almost all branches of science. However, until recently, NMR methodology was limited by the time constant T1 for the decay of nuclear spin magnetization through contact with the thermal molecular environment. Long-lived states, which are correlated quantum states of multiple nuclei, have decay time constants that may exceed T1 by large factors. Here we demonstrate a nuclear long-lived state comprising two 13C nuclei with a lifetime exceeding one hour in room-temperature solution, which is around 50 times longer than T1. This behavior is well-predicted by a combination of quantum theory, molecular dynamics, and quantum chemistry. Such ultra-long-lived states are expected to be useful for the transport and application of nuclear hyperpolarization, which leads to NMR and MRI signals enhanced by up to five orders of magnitude.

Long-Lived Nuclear Spin States in Methyl Groups and Quantum-Rotor-Induced Polarization

Substances containing rapidly rotating methyl groups may exhibit long-lived states (LLSs) in solution, with relaxation times substantially longer than the conventional spin-lattice relaxation time T1. The states become long-lived through rapid internal rotation of the CH3 group, which imposes an approximate symmetry on the fluctuating nuclear spin interactions. In the case of very low CH3 rotational barriers, a hyperpolarized LLS is populated by thermal equilibration at liquid helium temperature. Following dissolution, cross-relaxation of the hyperpolarized LLS, induced by heteronuclear dipolar couplings, generates strongly enhanced antiphase NMR signals. This mechanism explains the NMR signal enhancements observed for (13)C-γ-picoline (Icker, M.; Berger, S. J. Magn. Reson. 2012, 219, 1-3).

Theory of long-lived nuclear spin states in methyl groups and quantum-rotor induced polarisation

Long-lived nuclear spin states have a relaxation time much longer than the longitudinal relaxation time T1. Long-lived states extend significantly the time scales that may be probed with magnetic resonance, with possible applications to transport and binding studies, and to hyperpolarised imaging. Rapidly rotating methyl groups in solution may support a long-lived state, consisting of a population imbalance between states of different spin exchange symmetries. Here, we expand the formalism for describing the behaviour of long-lived nuclear spin states in methyl groups, with special attention to the hyperpolarisation effects observed in (13)CH3 groups upon rapidly converting a material with low-barrier methyl rotation from the cryogenic solid state to a room-temperature solution [M. Icker and S. Berger, J. Magn. Reson. 219, 1 (2012)]. We analyse the relaxation properties of methyl long-lived states using semi-classical relaxation theory. Numerical simulations are supplemented with a spherical-tensor analysis, which captures the essential properties of methyl long-lived states.

Enhancement of quantum rotor NMR signals by frequency-selective pulses.

Quantum-rotor-induced polarisation (QRIP) enhancement is exhibited by substances which contain freely rotating methyl groups in the solid state, provided that the methyl groups contain a (13)C nucleus. Strong signal enhancements are observed in solution NMR when the material is first equilibrated at cryogenic temperatures, then rapidly dissolved with a warm solvent and transferred into an NMR magnet. QRIP leads to strongly-enhanced (13)C NMR signals, but relatively weak enhancements of the (1)H signals. We show that the (1)H signals suffer from a partial cancellation of degenerate contributions, which may be corrected by applying a frequency-selective π pulse to the inner peaks of the (13)C multiplet prior to (1)H observation.

Direct enhancement of nitrogen-15 targets at high-field by fast ADAPT-SABRE

Graphical abstract

Alternating Delays Achieve Polarization Transfer (ADAPT) to heteronuclei in PHIP experiments

A new methodology for producing hyperpolarized 13C nuclei in small organic systems via parahydrogen induced polarization (PHIP) is proposed: ADAPT (Alternating Delays Achieve Polarization Transfer). The theoretical foundation of the process is investigated in some detail and experimental examples demonstrating the viability of the approach are provided as well. The number of adjustable parameters is fewer than most of other conversion schemes. The achieved theoretical heteronuclear polarization is close to unity for any examined magnetic equivalence regime. The duration of the pulse sequence, which was successfully implemented, can be shorter than other established methods reducing possible relaxation losses. The conversion scheme is robust to B1 inhomogeneities, but more sensitive to off-resonance RF irradiation.

Synthesis of an Isotopically Labeled Naphthalene Derivative That Supports a Long-Lived Nuclear Singlet State

The synthesis of an octa-alkoxy substituted isotopically labeled naphthalene derivative, shown to have excellent properties in singlet NMR experiments, is described. This highly substituted naphthalene system, which incorporates an adjacent 13C spin pair, is readily accessed from a commercially available 13C2-labeled building block via sequential thermal alkynyl- and arylcyclobutenone rearrangements. The synthetic route incorporates a simple desymmetrization approach leading to a small difference in the chemical shifts of the 13C spin pair, a design constraint crucial for accessing nuclear singlet order.

Dynamic nuclear polarization of long-lived nuclear spin states in methyl groups

We have induced hyperpolarized long-lived states in compounds containing 13C-bearing methyl groups by dynamic nuclear polarization (DNP) at cryogenic temperatures, followed by dissolution with a warm solvent. The hyperpolarized methyl long-lived states give rise to enhanced antiphase 13C NMR signals in solution, which often persist for times much longer than the 13C and 1H spin-lattice relaxation times under the same conditions. The DNP-induced effects are similar to quantum-rotor-induced polarization (QRIP) but are observed in a wider range of compounds because they do not depend critically on the height of the rotational barrier. We interpret our observations with a model in which nuclear Zeeman and methyl tunnelling reservoirs adopt an approximately uniform temperature, under DNP conditions. The generation of hyperpolarized NMR signals that persist for relatively long times in a range of methyl-bearing substances may be important for applications such as investigations of metabolism, enzymatic reactions, protein-ligand binding, drug screening, and molecular imaging.

Singlet order conversion and parahydrogen-induced hyperpolarization of 13C nuclei in near-equivalent spin systems.

We have demonstrated two radiofrequency pulse methods which convert the nuclear singlet order of proton spin pairs into the magnetisation of nearby 13C nuclei. These irradiation schemes work well in the near-equivalence regime of the three-spin system, which applies when the difference in the two 1H-13C couplings is much smaller than the 1H-1H coupling. We use pulse sequences to generate thermally polarized singlet states in a reproducible manner, and study the singlet-to-magnetisation transfer step. Preliminary results demonstrate a parahydrogen-enhanced 13C polarization level of at least 9%, providing a signal enhancement factor of more than 9000, using 50% enriched parahydrogen.

A pulse sequence for singlet to heteronuclear magnetization transfer: S2hM

We have recently demonstrated, in the context of para-hydrogen induced polarization (PHIP), the conversion of hyperpolarized proton singlet order into heteronuclear magnetisation can be efficiently achieved via a new sequence named S2hM (Singlet to heteronuclear Magnetisation). In this paper we give a detailed theoretical description, supported by an experimental illustration, of S2hM. Theory and experiments on thermally polarized samples demonstrate the proposed method is robust to frequency offset mismatches and radiofrequency field inhomogeneities. The simple implementation, optimisation and the high conversion efficiency, under various regimes of magnetic equivalence, makes S2hM an excellent candidate for a widespread use, particularly within the PHIP arena.