Harnessing polarisation transfer to indazole and imidazole through signal amplification by reversible exchange to improve their NMR detectability

The signal amplification by reversible exchange (SABRE) approach has been used to hyperpolarise the substrates indazole and imidazole in the presence of the co-ligand acetonitrile through the action of the precataysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)]. 2H-labelled forms of these catalysts were also examined. Our comparison of the two precatalysts [IrCl(COD)(IMes)] and [IrCl(COD)(SIMes)], coupled with 2H labelling of the N-heterocyclic carbene and associated relaxation and polarisation field variation studies, demonstrates the critical and collective role these parameters play in controlling the efficiency of signal amplification by reversible exchange. Ultimately, with imidazole, a 700-fold1H signal gain per proton is produced at 400 MHz, whilst for indazole, a 90-fold increase per proton is achieved. The co-ligand acetonitrile proved to optimally exhibit a 190-fold signal gain per proton in these measurements, with the associated studies revealing the importance the substrate plays in controlling this value

Long-lived States to Sustain SABRE Hyperpolarised Magnetisation

The applicability of the magnetic resonance (MR) technique in the liquid phase is limited by poor sensitivity and short nuclear spin coherence times which are insufficient for many potential applications. Here we illustrate how it is possible to address both of these issues simultaneously by harnessing long-lived hyperpolarised spin states that are formed by adapting the Signal Amplification by Reversible Exchange (SABRE) technique. We achieve more than 4 % net 1H-polarisation in a long-lived form that remains detectable for over ninety seconds by reference to proton pairs in the biologically important molecule nicotinamide and a pyrazine derivative whose in vivo imaging will offer a new route to probe disease in the futur

Investigating pyridazine and phthalazine exchange in a series of iridium complexes in order to define their role in the catalytic transfer of magnetisation from para-hydrogen

The reaction of [Ir(IMes)(COD)Cl], [IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, COD = 1,5-cyclooctadiene] with pyridazine (pdz) and phthalazine (phth) results in the formation of [Ir(COD)(IMes)(pdz)]Cl and [Ir(COD)(IMes)(phth)]Cl. These two complexes are shown by nuclear magnetic resonance (NMR) studies to undergo a haptotropic shift which interchanges pairs of protons within the bound ligands. When these complexes are exposed to hydrogen, they react to form [Ir(H)2(COD)(IMes)(pdz)]Cl and [Ir(H)2(COD)(IMes)(phth)]Cl, respectively, which ultimately convert to [Ir(H)2(IMes)(pdz)3]Cl and [Ir(H)2(IMes)(phth)3]Cl, as the COD is hydrogenated to form cyclooctane. These two dihydride complexes are shown, by NMR, to undergo both full N-heterocycle dissociation and a haptotropic shift, the rates of which are affected by both steric interactions and free ligand pKa values. The use of these complexes as catalysts in the transfer of polarisation from para-hydrogen to pyridazine and phthalazine via signal amplification by reversible exchange (SABRE) is explored. The possible future use of drugs which contain pyridazine and phthalazine motifs as in vivo or clinical magnetic resonance imaging probes is demonstrated; a range of NMR and phantom-based MRI measurements are reported

Coherent evolution of parahydrogen induced polarisation using laser pump, NMR probe spectroscopy : Theoretical framework and experimental observation

We recently reported a pump-probe method that uses a single laser pulse to introduce parahydrogen (p-H2) into a metal dihydride complex and then follows the time-evolution of the p-H2-derived nuclear spin states by NMR. We present here a theoretical framework to describe the oscillatory behaviour of the resultant hyperpolarised NMR signals using a product operator formalism. We consider the cases where the p-H2-derived protons form part of an AX, AXY, AXYZ or AA′XX′ spin system in the product molecule. We use this framework to predict the patterns for 2D pump-probe NMR spectra, where the indirect dimension represents the evolution during the pump-probe delay and the positions of the cross-peaks depend on the difference in chemical shift of the p-H2-derived protons and the difference in their couplings to other nuclei. The evolution of the NMR signals of the p-H2-derived protons, as well as the transfer of hyperpolarisation to other NMR-active nuclei in the product, is described. The theoretical framework is tested experimentally for a set of ruthenium dihydride complexes representing the different spin systems. Theoretical predictions and experimental results agree to within experimental error for all features of the hyperpolarised 1H and 31P pump-probe NMR spectra. Thus we establish the laser pump, NMR probe approach as a robust way to directly observe and quantitatively analyse the coherent evolution of p-H2-derived spin order over micro-to-millisecond timescales

Using Parahydrogen Induced Polarization to Study Steps in the Hydroformylation Reaction.

A range of iridium complexes, Ir(η3-C3H5)(CO)(PR2R’)2 (1a-1e) [where 1a, PR2R’ = PPh3, 1b P(p-tol)3, 1c PMePh2, 1d PMe2Ph and 1e PMe3] were synthesized and their reactivity as stoichiometric hydroformylation precursors studied. Para-hydrogen assisted NMR spectroscopy detected the following intermediates: Ir(H)2(η3-C3H5)(CO)(PR2R’) (2a-e), Ir(H)2(η1-C3H5)(CO)(PR2R’)2 (4d-e), Ir(H)2(η1-C3H5)(CO)2(PR2R’) (10a-e), Ir(H)2(CO-C3H5)(CO)2(PR2R’) (11a-c), Ir(H)2(CO-C3H7)(CO)2(PR2R’) (12a-c) and Ir(H)2(CO-C3H5)(CO)(PR2R’)2 (13d-e). Some of these species exist as two geometric isomers according to their multinuclear NMR characteristics. The NMR studies suggest a role for the following 16 electron species in these reactions: Ir(η3-C3H5)(CO)(PR2R’), Ir(η1-C3H5)(CO)(PR2R’)2, Ir(η1-C3H5)(CO)2(PR2R’), Ir(CO-C3H5)(CO)2(PR2R’), Ir(CO-C3H7)(CO)2(PR2R’) and Ir(CO-C3H5)(CO)(PR2R’)2. Their role is linked to several 18 electron species in order to confirm the route by which hydroformylation and hydrogenation proceeds

Achieving High Levels of NMR-Hyperpolarization in Aqueous Media With Minimal Catalyst Contamination via SABRE

Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1H NMR signals in a range of substrates in aqueous media. In order to achieve this outcome phase-transfer-catalysis is exploited which leads to less than less than 1.5 x 10-6 mol dm-3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called CAtalyst Separated Hyperpolarization via Signal Amplification By Reversible Exchange or CASH-SABRE. We illustrate this method for the substrates pyrazine, 5-methylpyrimidine, 4,6-d2-methyl nicotinate, 4,6-d2-nicotinamide and pyridazine achieving 1H signals gains of approximately 790-, 340-, 3000-, 260- and 380-fold per proton at 9.4 T at the time point where phase separation is complete

Improving the hyperpolarization of (31)p nuclei by synthetic design

Traditional (31)P NMR or MRI measurements suffer from low sensitivity relative to (1)H detection and consequently require longer scan times. We show here that hyperpolarization of (31)P nuclei through reversible interactions with parahydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold (31)P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan (31)P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal-to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal-to-noise ratio of just 11.4. (31)P-hyperpolarized images are also reported from a 7 T preclinical scanner

Hyperpolarization methods for MRS

© 2015 John Wiley & Sons, Ltd. This article covers the fundamental principles and practice of NMR hyperpolarization techniques, which are proving useful for in vivo magnetic resonance spectroscopy (MRS) studies of metabolism in animal models, and clinical trials with hyper-enhanced sensitivity. Fundamentally, hyperpolarization methods enhance nuclear spin polarization by orders-of-magnitude, resulting in concomitant improvement in NMR detection sensitivity. The hyperpolarization methods described here - dynamic nuclear polarization (DNP), para-hydrogen induced polarization (PHIP), signal amplification by reversible exchange (SABRE), and spin-exchange optical pumping (SEOP) - are capable of achieving nuclear spin polarization approaching the theoretical maximum of unity on nuclear spin sites of molecular or atomic agents suitable for in vivo administration. Importantly, hyperpolarization is inherently nonequilibrium in nature: The duration of the hyperpolarization is frequently shortlived, often being limited by the in vivo spin-lattice relaxation times (T 1) that are on the order of seconds to a minute. Nevertheless, sufficient amounts of nuclear spin polarization can survive the process of preparation, administration, and in vivo circulation to provide extraordinary enhancement of the hyperpolarized agent. The chemical shift dispersion of these agents at the molecular location of interest reports on functional, metabolic, and other processes at the molecular level, enabling true molecular MRS imaging

Iridium α-carboxyimine complexes hyperpolarized with parahydrogen exist in nuclear singlet states before conversion into iridium carbonates

The formation and hyperpolarization of an [Ir(H)2(amine)(IMes)(η2-imine)]Cl complex that can be created in a hyperpolarized nuclear singlet state is reported. These complexes are formed when an equilibrium mixture of pyruvate, amine (benzylamine or phenylethylamine), and the corresponding imine condensation product, react with preformed [Ir(H)2(amine)3(IMes)]Cl. These iridium -carboxyimine complexes exist as two regioisomers differentiated by the position of amine. When examined with para-hydrogen the hydride resonances of the isomer with amine trans to hydride become strongly hyperpolarized. The initial hydride singlet states readily transfer to the corresponding 13C2 state in the labelled imine and exhibit magnetic state lifetimes of up to 11 seconds. Their 13C signals have been detected with up to 420 fold signal gains at 9.4 T. On a longer timescale, and in the absence of H2, further reaction leads to the formation of neutral carbonate containing [Ir(amine)(η2-CO3)(IMes)(η2-imine)]. Complexes are characterized by, IR, MS, NMR and X-ray diffraction

NMR hyperpolarization techniques of gases

Nuclear spin polarization can be significantly increased through the process of hyperpolarization, leading to an increase in the sensitivity of nuclear magnetic resonance (NMR) experiments by 4–8 orders of magnitude. Hyperpolarized gases, unlike liquids and solids, can often be readily separated and purified from the compounds used to mediate the hyperpolarization processes. These pure hyperpolarized gases enabled many novel MRI applications including the visualization of void spaces, imaging of lung function, and remote detection. Additionally, hyperpolarized gases can be dissolved in liquids and can be used as sensitive molecular probes and reporters. This Minireview covers the fundamentals of the preparation of hyperpolarized gases and focuses on selected applications of interest to biomedicine and materials science