Dataset Information

Effects of Deuteration of 13C-Enriched Phospholactate on Efficiency of Parahydrogen-Induced Polarization by Magnetic Field Cycling.

ABSTRACT: We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-13C-phosphoenolpyruvate and 1-13C-phosphoenolpyruvate-d2 for application in hyperpolarized imaging technology. The 1-13C-phosphoenolpyruvate-d2 was synthesized with 57% overall yield (over two steps), and >98% 2H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-13C-phosphoenolpyruvate. These two unsaturated compounds with C=C bonds were employed for parahydrogen-induced polarization via pairwise parahydrogen addition in aqueous medium. We find that deuteration of 1-13C-phosphoenolpyruvate resulted in overall increase of 1H T1 of nascent hyperpolarized protons (4.30 ± 0.04 s versus 2.06 ± 0.01 s) and 1H polarization (~2.5% versus ~0.7%) of the resulting hyperpolarized 1-13C-phospholactate. The nuclear spin polarization of nascent parahydrogen-derived protons was transferred to 1-13C nucleus via magnetic field cycling procedure. The proton T1 increase in hyperpolarized deuterated 1-13C-phospholactate yielded approximately 30% better 13C polarization compared to non-deuterated hyperpolarized 1-13C-phospholactate. Analysis of T1 relaxation revealed that deuteration of 1-13C-phospholactate may have resulted in approximately 3-fold worse H?13C polarization transfer efficiency via magnetic field cycling. Since magnetic field cycling is a key polarization transfer step in the Side-Arm Hydrogenation approach, the presented findings may guide more rationale design of contrast agents using parahydrogen polarization of a broad range of 13C hyperpolarized contrast agents for molecular imaging employing 13C MRI. The hyperpolarized 1-13C-phospholactate-d2 is of biomedical imaging relevance because it undergoes in vivo dephosphorylation and becomes 13C hyperpolarized lactate, which as we show can be detected in the brain using 13C hyperpolarized MRI; an implication for future imaging of neurodegenerative diseases and dementia.

SUBMITTER: Salnikov OG

PROVIDER: S-EPMC6707357 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Effects of Deuteration of 13C-Enriched Phospholactate on Efficiency of Parahydrogen-Induced Polarization by Magnetic Field Cycling.

Salnikov Oleg G OG Shchepin Roman V RV Chukanov Nikita V NV Jaigirdar Lamya L Pham Wellington W Kovtunov Kirill V KV Koptyug Igor V IV Chekmenev Eduard Y EY

The journal of physical chemistry. C, Nanomaterials and interfaces 20181002 43

We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-13C-phosphoenolpyruvate and 1-13C-phosphoenolpyruvate-d2 for application in hyperpolarized imaging technology. The 1-13C-phosphoenolpyruvate-d2 was synthesized with 57% overall yield (over two steps), and >98% 2H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-13C-phosphoenolpyruvate. Th ...[more]

PMID: 31447960

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Project description:This study was designed to determine the effects of deuteration in pyruvate on exchange reactions in alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and flux through pyruvate dehydrogenase (PDH). Although deuteration of a 13C enriched substrate is commonly used to increase the lifetime of a probe for hyperpolarization experiments, the potential impact of kinetic isotope effects on such substitutions has not been studied in detail. Metabolism of deuterated pyruvate was investigated in isolated rat hearts. Hearts were perfused with a 1:1 mixture of [U-13C3]pyruvate and [2-13C1]pyruvate or a 1:1 mixture of [U-13C3]pyruvate plus [2-13C1, U-2H3]pyruvate for 30?min before being freeze clamped. Another set of hearts received [2-13C1, U-2H3]pyruvate and was freeze-clamped at 3?min or 6?min. Tissue extracts were analyzed by 1H and 13C{1H} NMR spectroscopy. The chemical shift isotope effect of 2H was monitored in the 13C NMR spectra of the C2 resonance of lactate and alanine plus the C5 of glutamate. There was little kinetic isotope effect of 2H in pyruvate on flux through PDH, LDH or ALT as detected by the distribution of 13C, but the distribution of 2H differed markedly between alanine and lactate. At steady-state, alanine was a mixture of deuterated species, while lactate was largely perdeuterated. Consistent with results at steady-state, hearts freeze-clamped at 3?min or 6?min showed rapid removal of deuterium in alanine but not in lactate. Metabolism of hyperpolarized [1-13C1]pyruvate was compared to [1-13C1,U-2H3]pyruvate in isolated hearts. Consistent with the results from tissue extracts, there was little effect of deuteration on the kinetics of appearance of lactate, alanine or bicarbonate, but there was a small, time-dependent upfield chemical shift in the HP[1-13C1]alanine signal reflecting exchange of methyl deuterons with water protons. Together, these results demonstrate that (1) the kinetics of pyruvate metabolism in hearts detected by 13C NMR are not affected by replacement of the pyruvate methyl protons with deuterons and (2) that the loss of deuterium from the methyl position occurs rapidly during the conversion of pyruvate to alanine. The majority of the deuterium atoms are lost on the time-scale of a hyperpolarization experiment.

Project description:MR techniques using hyperpolarized (13)C have successfully produced examples of angiography and intermediary metabolic imaging, but, to date, no receptor imaging has been attempted. The goal of this study was to synthesize and evaluate a novel hyperpolarizable molecule, 2,2,3,3-tetrafluoropropyl 1-(13)C-propionate-d(2,3,3) (TFPP), for the detection of atheromatous plaques in vivo. TFPP binds to lipid bilayers and its use in hyperpolarized MR could prove to be a major step towards receptor imaging. The precursor, 2,2,3,3-tetrafluoropropyl 1-(13)C-acrylate-d(2,3,3) (TFPA), binds to 1,2-dimyristoylphosphatidylcholine lipid bilayers with a 1.6-ppm chemical shift in the (19)F MR spectrum. This molecule was designed to be hyperpolarized through the addition of parahydrogen to the (13)C-acrylate moiety by parahydrogen-induced polarization. TFPA was hyperpolarized to TFPP to an extent similar to that of the hydroxyethylacrylate to hydroxyethylpropionate transition: 17 ± 4% for TFPP versus 20% for hydroxyethylpropionate; T(1) relaxation times (45 ± 2 s versus 55 ± 2 s) were comparable and the hyperpolarized properties of TFPP were characterized. Hydroxyethylacrylate, like TFPA, has a chemical structure with an acrylate moiety, but does not contain the lipid-binding tetrafluoropropyl functional group. Hyperpolarized TFPP binds to the lipid bilayer, appearing as a second, chemically shifted (13)C hyperpolarized MR signal with a further reduction in the longitudinal relaxation time (T(1) = 21 ± 1 s). In aortas harvested from low-density lipoprotein receptor knock-out mice fed with a high-fat diet for 9 months, and in which atheroma is deposited in the aorta and heart, TFPP showed greater binding to lipid on the intimal surface than in control mice fed a normal diet. When TFPP was hyperpolarized and administered in vivo to atheromatous mice in a pilot study, increased binding was observed on the endocardial surface of the intact heart compared with normally fed controls. Hyperpolarized TFPP has bio-sensing specificity for lipid, coupled with a 42,000-fold sensitivity gain in the MR signal at 4.7 T. Binding of TFPP with lipids results in the formation of a characteristic second peak in MRS. TFPP therefore has the potential to act as an in vivo molecular probe for atheromatous plaque imaging and may serve as a model of receptor-targeted bio-imaging with enhanced MR sensitivity.

Dataset Information

Effects of Deuteration of 13C-Enriched Phospholactate on Efficiency of Parahydrogen-Induced Polarization by Magnetic Field Cycling.

Publications

Effects of Deuteration of <sup>13</sup>C-Enriched Phospholactate on Efficiency of Parahydrogen-Induced Polarization by Magnetic Field Cycling.

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