Hyperpolarisation of weakly binding N-heterocycles using signal amplification by reversible exchange.
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ABSTRACT:
SUBMITTER: Rayner PJ
PROVIDER: S-EPMC8179664 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Here we present the feasibility of NMR signal amplification by reversible exchange (SABRE) using radio frequency irradiation at low magnetic field (0.05 T) in the regime where the chemical shifts of free and catalyst-bound species are similar. In SABRE, the 15N-containing substrate and parahydrogen perform simultaneous chemical exchange on an iridium hexacoordinate complex. A shaped spin-lock induced crossing (SLIC) radio frequency pulse sequence followed by a delay is applied at quasi-resonance (QUASR) conditions of 15N spins of a 15N-enriched substrate. As a result of this pulse sequence application, 15N z-magnetization is created from the spin order of parahydrogen-derived hyperpolarized hydrides. The repetition of the pulse sequence block consisting of a shaped radio frequency pulse and the delay leads to the buildup of 15N magnetization. The modulation of this effect by the irradiation frequency, pulse duration and amplitude, delay duration, and number of pumping cycles was demonstrated. Pyridine-15N, acetonitrile-15N, and metronidazole-15N2-13C2 substrates were studied representing three classes of compounds (five- and six-membered heterocycles and nitrile), showing the wide applicability of the technique. Metronidazole-15N2-13C2 is an FDA-approved antibiotic that can be injected in large quantities, promising noninvasive and accurate hypoxia sensing. The 15N hyperpolarization levels attained with QUASR-SABRE on metronidazole-15N2-13C2 were more than 2-fold greater than those with SABRE-SHEATH (SABRE in shield enables alignment transfer to heteronuclei), demonstrating that QUASR-SABRE can deliver significantly more efficient means of SABRE hyperpolarization.
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Project description:Hyperpolarization methods are used in NMR to overcome its inherent sensitivity problem. Herein, the biologically relevant target nicotinamide is polarized by the hyperpolarization technique signal amplification by reversible exchange. We illustrate how the polarization transfer field, and the concentrations of parahydrogen, the polarization-transfer-catalyst and substrate can be used to maximize signal amplification by reversible exchange effectiveness by reference to the first-order spin system of this target. The catalyst is shown to be crucial in this process, first by facilitating the transfer of hyperpolarization from parahydrogen to nicotinamide and then by depleting the resulting polarized states through further interaction. The 15 longitudinal one, two, three and four spin order terms produced are rigorously identified and quantified using an automated flow apparatus in conjunction with NMR pulse sequences based on the only parahydrogen spectroscopy protocol. The rates of build-up of these terms were shown to follow the order four~three > two > single spin; this order parallels their rates of relaxation. The result of these competing effects is that the less-efficiently formed single-spin order terms dominate at the point of measurement with the two-spin terms having amplitudes that are an order of magnitude lower. We also complete further measurements to demonstrate that (13)C NMR spectra can be readily collected where the long-lived quaternary (13)C signals appear with significant intensity. These are improved upon by using INEPT. In summary, we dissect the complexity of this method, highlighting its benefits to the NMR community and its applicability for high-sensitivity magnetic resonance imaging detection in the future.
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Project description:A novel variant of an iridium-based organometallic catalyst was synthesized and used to enhance the NMR signals of pyridine in a heterogeneous phase by immobilization on polymer microbead solid supports. Upon administration of parahydrogen (pH2) gas to a methanol mixture containing the HET-SABRE catalyst particles and the pyridine, up to fivefold enhancements were observed in the (1)H NMR spectra after sample transfer to high field (9.4 T). Importantly, enhancements were not due to any residual catalyst molecules in solution, thus supporting the true heterogeneity of the SABRE process. Further significant improvements may be expected by systematic optimization of experimental parameters. Moreover, the heterogeneous catalyst is easy to separate and recycle, thus opening a door to future potential applications varying from spectroscopic studies of catalysis, to imaging metabolites in the body without concern of contamination from expensive and potentially toxic metal catalysts or accompanying organic molecules.
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Project description:Here we report the polarization of the solvent OH protons by SABRE using standard iridium-based catalysts under slightly acidic conditions. Solvent polarization was observed in the presence of a variety of structurally similar N-donor substrates while no solvent enhancement was observed in the absence of substrate or para-hydrogen (p-H2). Solvent polarization was sensitive to the polarizing field and catalyst:substrate ratio in a manner similar to that of substrate protons. SABRE experiments with pyridine-d5 suggest a mechanism where hyperpolarization is transferred from the free substrate to the solvent by chemical exchange while measured hyperpolarization decay times suggest a complimentary mechanism which occurs by direct coordination of the solvent to the catalytic complex. We found the solvent hyperpolarization to decay nearly 3 times more slowly than its characteristic spin-lattice relaxation time suggesting that the hyperpolarized state of the solvent may be sufficiently long lived (∼20s) to hyperpolarize biomolecules having exchangeable protons. This route may offer future opportunities for SABRE to impact metabolic imaging.
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Project description:We report on an extension of the quasi-resonance (QUASR) pulse sequence used for signal amplification by reversible exchange (SABRE), showing that we may target distantly J-coupled 19F-spins. Polarization transfer from the parahydrogen-derived hydrides to the 19F nucleus is accomplished via weak five-bond J-couplings using a shaped QUASR radio frequency pulse at a 0.05 T magnetic field. The net result is the direct generation of hyperpolarized 19F z-magnetization, derived from the parahydrogen singlet order. An accumulation of 19F polarization on the free ligand is achieved with subsequent repetition of this pulse sequence. The hyperpolarized 19F signal exhibits clear dependence on the pulse length, irradiation frequency, and delay time in a manner similar to that reported for 15N QUASR-SABRE. Moreover, the hyperpolarized 19F signals of 3-19F-14N-pyridine and 3-19F-15N-pyridine isotopologues are similar, suggesting that (i) polarization transfer via QUASR-SABRE is irrespective of the nitrogen isotopologue and (ii) the presence or absence of the spin-1/2 15N nucleus has no impact on the efficiency of QUASR-SABRE polarization transfer. Although optimization of polarization transfer efficiency to 19F (P19F ? 0.1%) was not the goal of this study, we show that high-field SABRE can be efficient and broadly applicable for direct hyperpolarization of 19F spins.
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Project description: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 13 C pyruvate signal enhancements in seconds through the formation of the novel polarisation transfer catalyst [Ir(H)2 (?2 -pyruvate)(DMSO)(IMes)]. By harnessing SABRE, strong signals for [1-13 C]- and [2-13 C]pyruvate in addition to a long-lived singlet state in the [1,2-13 C2 ] 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.
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