Deuteration of Hyperpolarized <sup>13</sup>C‐Labeled Zymonic Acid Enables Sensitivity‐Enhanced Dynamic MRI of pH

Hundshammer, Christian; Düwel, Stephan; Köcher, Simone Swantje; Gersch, Malte; Feuerecker, Benedikt; Scheurer, Christoph; Haase, Axel; Glaser, Steffen J.; Schwaiger, Markus; Schilling, Franz

doi:10.1002/cphc.201700956

Cited by 8 publications

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“…17 Although in this way the dependency on PDH activity is eliminated, 17 the uncertainty in intracellular versus extracellular pH, and the dependency on CA activity, remain. 18 Hyperpolarized [1,5-13 C 2 ]zymonic acid has been shown to be a sensitive extracellular pH marker that is independent of enzymatic activity 19 and was found useful in vivo in the rat bladder, kidney, and in adenocarcinoma. 20 Several other enzymatically independent hyperpolarized pH reporters have also been investigated, [21][22][23][24][25][26][27] but were only tested in vitro.…”

Section: Introductionmentioning

confidence: 99%

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

et al. 2020

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Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can assess blood flow, heart anatomy and mechanical function. However, for early diagnosis and improved treatment, further functional biomarkers are needed. One such functional biomarker could be the myocardium pH. Although tissue pH is already determinable via MR techniques, and has been since the early 1990s, it remains elusive to use practically. The objective of this study was to explore the possibility to evaluate cardiac pH noninvasively, using in-cell enzymatic rates of hyperpolarized [1-13 C]pyruvate metabolism (ie, moles of product produced per unit time) determined directly in real time using magnetic resonance spectroscopy in a perfused mouse heart model. As a gold standard for tissue pH we used 31 P spectroscopy and the chemical shift of the inorganic phosphate (Pi) signal. The nonhomogenous pH distribution of the perfused heart was analyzed using a multiparametric analysis of this signal, thus taking into account the heterogeneous nature of this characteristic. As opposed to the signal ratio of hyperpolarized [ 13 C]bicarbonate to [ 13 CO 2 ], which has shown correlation to pH in other studies, we investigated here the ratio of two intracellular enzymatic rates: lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), by way of determining the production rates of [1-13 C]lactate and [ 13 C]bicarbonate, respectively. The enzyme activities determined here are intracellular, while the pH determined using the Pi signal may contain an extracellular component, which could not be ruled out. Nevertheless, we report a strong correlation between the tissue pH and the LDH/PDH activities ratio. This work may pave the way for using the LDH/PDH activities ratio as an indicator of cardiac intracellular pH in vivo, in an MRI examination.

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Section: Introductionmentioning

confidence: 99%

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

et al. 2020

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“…However, other 13 C nuclei, especially those with directly attached protons, are not feasible HP 13 C probes due to very short T 1 ’s (less than 5s). 14 One approach to increase T 1 is the substitution of 1 H with 2 H (or D), a quadrupolar nucleus with a gyromagnetic ratio γ about 6.5-fold smaller than the one for 1 H. 15–29 This use of deuterated substrates has proved particularly fruitful in the case of SABRE 13 and PHIP 11,12 methods. This approach is effective when dipolar 13 C- 1 H coupling contributes substantially to T 1 relaxation.…”

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confidence: 99%

Late-stage deuteration of¹³C-enriched substrates forT₁prolongation in hyperpolarized¹³C MRI

et al. 2018

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A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin-lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C]valine), significant increase of their T1 was observed at 3 T with deuterium labeling (+26%, 22%, +16%, +25% and +29%, respectively). Remarkably, in the case of [2-13C]alanine, [2-13C]serine and [2-13C]lactate, deuterium labeling led to a greater than four fold increase in T1. [1-13C,2-2H]alanine, produced using this method, was applied to in vitro enzyme assays with alanine aminotransferase, demonstrating a kinetic isotope effect.

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“…Another metabolic property of tumors resulting from the Warburg effect is the export of excess lactate to the extracellular space, which leads to an acidification of the tumor microenvironment. Extracellular pH can be probed by hyperpolarized pH sensors, whose NMR signals either exhibit a ratiometric ([ 13 C]bicarbonate/[ 13 C]CO 2 pair [5]) pH-sensitivity or pH-dependent chemical shifts ([1,5- 13 C] zymonic acid [50,351]). Because chemical shift based pHsensors require high spectral resolution and exhibit chemical shifts that are not known prior to measurement, FID-CSI is often used as the imaging strategy [352].…”

Section: Dissolution Dynamic Nuclear Polarization (Ddnp)mentioning

confidence: 99%

Acquisition strategies for spatially resolved magnetic resonance detection of hyperpolarized nuclei

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et al. 2019

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Hyperpolarization is an emerging method in magnetic resonance imaging that allows nuclear spin polarization of gases or liquids to be temporarily enhanced by up to five or six orders of magnitude at clinically relevant field strengths and administered at high concentration to a subject at the time of measurement. This transient gain in signal has enabled the non-invasive detection and imaging of gas ventilation and diffusion in the lungs, perfusion in blood vessels and tissues, and metabolic conversion in cells, animals, and patients. The rapid development of this method is based on advances in polarizer technology, the availability of suitable probe isotopes and molecules, improved MRI hardware and pulse sequence development. Acquisition strategies for hyperpolarized nuclei are not yet standardized and are set up individually at most sites depending on the specific requirements of the probe, the object of interest, and the MRI hardware. This review provides a detailed introduction to spatially resolved detection of hyperpolarized nuclei and summarizes novel and previously established acquisition strategies for different key areas of application.

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Deuteration of Hyperpolarized ¹³C‐Labeled Zymonic Acid Enables Sensitivity‐Enhanced Dynamic MRI of pH

Cited by 8 publications

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Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

Late-stage deuteration of¹³C-enriched substrates forT₁prolongation in hyperpolarized¹³C MRI

Acquisition strategies for spatially resolved magnetic resonance detection of hyperpolarized nuclei

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Deuteration of Hyperpolarized 13C‐Labeled Zymonic Acid Enables Sensitivity‐Enhanced Dynamic MRI of pH

Cited by 8 publications

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Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

Correlation between lactate dehydrogenase/pyruvate dehydrogenase activities ratio and tissue pH in the perfused mouse heart: A potential noninvasive indicator of cardiac pH provided by hyperpolarized magnetic resonance

Late-stage deuteration of13C-enriched substrates forT1prolongation in hyperpolarized13C MRI

Acquisition strategies for spatially resolved magnetic resonance detection of hyperpolarized nuclei

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Deuteration of Hyperpolarized ¹³C‐Labeled Zymonic Acid Enables Sensitivity‐Enhanced Dynamic MRI of pH

Late-stage deuteration of¹³C-enriched substrates forT₁prolongation in hyperpolarized¹³C MRI