In vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-13C]alanine

Hu, Simon; Zhu, Minhua; Yoshihara, Hikari A.I.; Wilson, David M.; Keshari, Kayvan R.; Shin, Peter; Reed, Galen D.; Morze, Cornelius von; Bok, Robert; Larson, Peder E. Z.; Kurhanewicz, John; Vigneron, Daniel B.

doi:10.1016/j.mri.2011.07.001

Cited by 36 publications

(47 citation statements)

References 13 publications

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“…The extracellular space (ECS) volume fraction varies with tissue and physiological state, being about 20% in brain and up to 70% in tumor (8,9). A significant increase in the lactate/pyruvate ratio when using hyperpolarized [1-13 C]alanine compared to hyperpolarized [1-13 C]pyruvate have been reported in rats (10). This results support the significant contribution to HP-NMR signals by extracellular pyruvate that does not involve in LDH reaction directly.…”

supporting

confidence: 61%

A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance

2016

Quant. Imaging Med. Surg.

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Hyperpolarized nuclear magnetic resonance (HP-NMR) can probe the reaction kinetics of metabolic enzymes in vivo (1), and the translation of this technology into human patients based on the most commonly used tracer 13 C-pyruvate has been initiated in recent years (2). Currently the metabolite signal ratios are used as indicators for biological processes in healthy and diseased status. For example, to probe the reaction of lactate dehydrogenase (LDH) with hyperpolarized 13 C-pyruvate, the peak, mean, or integrated (area-undercurve) signal ratios of 13 C-lactate to 13 C-pyruvate are used to differentiate tumor and normal tissues, and to evaluate treatment response (3-5). However, these ratios do not have clearly defined biochemical meaning, and it is desirable to quantify the reaction rate constants. The accurate determination of reaction rate constants remains a challenge. The first-order rate constants of LDH reaction have been quantified in tissues by modeling the signal time courses of hyperpolarized 13 C-labeled pyruvate and lactate (3-7). Nevertheless, the rate constant quantification suffers from inaccuracy for the following reasons:  Both intracellular and extracellular 13 C-labeled pyruvate contributes to the detected HP-NMR signal, but it is the intracellular pyruvate that is coupled to the LDH reaction in the cell. The extracellular space (ECS) volume fraction varies with tissue and physiological state, being about 20% in brain and up to 70% in tumor (8,9). A significant increase in the lactate/pyruvate ratio when using hyperpolarized [1-13 C]alanine compared to hyperpolarized [1-13 C]pyruvate have been reported in rats (10). This results support the significant contribution to HP-NMR signals by extracellular pyruvate that does not involve in LDH reaction directly. The modeling of hyperpolarized pyruvate signals without differentiating signals from intracellular and ECS will underestimate the reaction rate constant for the conversion of pyruvate to lactate. This underestimation is expected to be particularly severe for some perfused organ studies using non-selective radiofrequency pulses for signal acquisition (5);  The transport of tracer from blood to interstitial space, and then through cell membrane to intracellular space complicates the mathematical modeling of enzyme kinetics. The rate constants determined for LDH by the two-site exchange modeling are really apparent rate constants, depending on the speeds of these transport processes (11). To determine the kinetic constants of an intracellular enzyme in vivo more accurately by HP-NMR, here I propose a simple pre-tracer approach to remove the complexities caused by extracellular metabolite signals and transport processes. Generally speaking, a hyperpolarized isotopelabeled pre-tracer (A), once it enters the space of interest (e.g., inside the cell), will be converted to the tracer of interest (B) via a local chemical reaction (e.g., by an intracellular enzyme E 1 ) ( Figure 1A). The tracer B will then be converted into additional metabolites of ...

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confidence: 61%

A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance

2016

Quant. Imaging Med. Surg.

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“…1) were each dissolved in three different solvents; either pure water, 99.9 % deuterated water or partially deuterated water with roughly 3 M water proton concentration, i.e., comparable to the methyl proton concentration of the metabolites. These molecules are of general interest as DNP targets because of their use in hyperpolarized metabolic imaging experiments [9,19]. Because of this, their size and their ease of handling they are ideal for our investigation of liquid DNP polarization transfer to small target molecules in solution.…”

Section: Resultsmentioning

confidence: 99%

“…However, high magnetic fields are needed for modern NMR applications for resolution and sensitivity reasons. At high magnetic fields, the pioneering work has been performed in the solid state [4,5] sparking a surge of new developments and applications [6][7][8][9]. This success triggered attempts to investigate also the potential of DNP in the liquid state at high magnetic fields, e.g., at 3.4 T [10-13] and 9.2 T [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Liquid State DNP on Metabolites at 260 GHz EPR/400 MHz NMR Frequency

2012

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We have performed liquid state (''Overhauser'') dynamic nuclear polarization (DNP) experiments at high magnetic field (9.2 T, corresponding to 260 GHz EPR and 400 MHz 1 H-NMR resonance frequency) on solutions of pyruvate, lactate and alanine in water with TEMPOL nitroxide radicals as polarizing agent. We present experimental results showing DNP enhancement on metabolite methyl protons, varying for the different target metabolites. It is shown that the enhancements are achieved through direct coupling between the radicals and the target metabolites in solution, i.e., the effect is not mediated by the solvent water protons. The coupling factors between the TEMPOL radicals and the metabolites observed are a factor of 3-5 smaller compared to direct polarization transfer from TEMPOL to water protons.

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“…Upon injection, HP [1- 13 C]alanine is converted to HP [1- 13 C]pyruvate via ALT, which can then be converted to HP [1- 13 C]lactate. Using HP [1- 13 C]alanine is advantageous as it allows relative measurements of endogenous pyruvate and lactate pool size [186] without the analytical difficulties arising from the large extracellular pyruvate signal. Alanine’s metabolism varies by organ, but ALT is especially active in the muscle and liver, which play a key role in the Cahill cycle that shuttles alanine and glucose between the two organs [187].…”

Section: Hyperpolarized Probes Used For Metabolic Studiesmentioning

confidence: 99%

“…An HP [1- 13 C]pyruvate study of the rat liver in the fed (high blood glucose) and fasted (low blood glucose) states demonstrated this process in vivo by detecting the expected decrease in alanine pool size via a decrease in HP alanine labeling in the fasted state [186]. The liver is also one of the few organs that expresses pyruvate carboxylase (PC) and phosphoenolpyruvate carboxykinase (PEPCK), allowing conversion of HP [1- 13 C]pyruvate to [1- 13 C]oxaloacetate and additional downstream metabolites ([1- 13 C]malate, [4- 13 C]malate and [1- 13 C]aspartate) (figure D) [178].…”

Section: Hyperpolarized Studies By Organ Systemmentioning

confidence: 99%

The use of hyperpolarized carbon-13 magnetic resonance for molecular imaging

Siddiqui

Kadlecek

Pourfathi

et al. 2017

Advanced Drug Delivery Reviews

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Until recently, molecular imaging using magnetic resonance (MR) has been limited by the modality’s low sensitivity, especially with non-proton nuclei. The advent of hyperpolarized (HP) MR overcomes this limitation by substantially enhancing the signal of certain biologically important probes through a process known as external nuclear polarization, enabling real-time assessment of tissue function and metabolism. The metabolic information obtained by HP MR imaging holds significant promise in the clinic, where it could play a critical role in disease diagnosis and therapeutic monitoring. This review will provide a comprehensive overview of the developments made in the field of hyperpolarized MR, including advancements in polarization techniques and delivery, probe development, pulse sequence optimization, characterization of healthy and diseased tissues, and the steps made towards clinical translation.

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In vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-13C]alanine

Cited by 36 publications

References 13 publications

A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance

A pre-tracer approach for improving the accuracy of metabolic measurements by hyperpolarized nuclear magnetic resonance

Liquid State DNP on Metabolites at 260 GHz EPR/400 MHz NMR Frequency

The use of hyperpolarized carbon-13 magnetic resonance for molecular imaging

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