Biomolecular imaging of 13C-butyrate with dissolution-DNP: Polarization enhancement and formulation for in vivo studies

Flori, Alessandra; Giovannetti, Giulio; Santarelli, Maria Filomena; Aquaro, Giovanni Donato; Marchi, Daniele De; Burchielli, Silvia; Frijia, Francesca; Positano, Vincenzo; Landini, Luigi; Menichetti, Luca

doi:10.1016/j.saa.2018.03.014

Cited by 9 publications

(49 citation statements)

References 60 publications

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“…Here, we observed that Δ(P + ,P À ) at the optimal Gd 3 + concentration were similarly reduced for both formulations (Supporting Figure S2D). Flori et al [34] have also reported asymmetric changes to the polarization of [1-13 C] butyric acid due to Gd 3 + doping. Here, Gd 3 + affected the intensity profiles of both formulations asymmetri- cally as well ( Figure S2E, Table S2).…”

Section: Discussionsupporting

confidence: 71%

“…Here, Gd 3 + affected the intensity profiles of both formulations asymmetri- cally as well ( Figure S2E, Table S2). Flori et al [34] have also reported asymmetric changes to the polarization of [1-13 C] butyric acid due to Gd 3 + doping. [27] Thus, the effect of Gd 3 + doping on the Δ(P + ,P À ) and the asymmetry of the intensity profile resembled prior studies and the differences may be attributed to the different sample compositions.…”

Section: Discussionmentioning

confidence: 97%

“…An investigation of the intensity profile shape for different formulations without lanthanide ion doping was reported by Flori et al [34] who showed a decrease in Δ(P + ,P À ) when the concentration of DMSO in a formulation of 8.3 M 20 % [1-13 C] butyric acid was increased from 1.87 M to 2.81 M and c.a. 4-fold improvement in the maximum polarization.…”

Section: Discussionmentioning

confidence: 99%

“…In 2008 Ardenkjaer-Larsen et al [27] showed for [1-13 C] pyruvic acid that the solid-state 13 C polarization obtained at 3.35 T can be improved � 1.6-fold by addition of a small amount of Gd 3 + in addition to the trityl free radical. [34] This effect depends on the magnetic field value [35,36] and the theoretical basis of this effect is still being researched. [34] This effect depends on the magnetic field value [35,36] and the theoretical basis of this effect is still being researched.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent studies performed at 3.35 T have confirmed the benefits of Gd 3 + doping of [1-13 C]pyruvic acid [28,29] and shown that it also improves the solid-state polarization of [ 13 C]urea, [30] [1-13 C] acetate, [31][32][33] and [1-13 C]butyrate. [34] This effect depends on the magnetic field value [35,36] and the theoretical basis of this effect is still being researched. [26,30,37] Although in many of the studies of hyperpolarized [ 13 C 6 , 2 H 7 ]glucose the authors have reported addition of small concentrations of Gd 3 + to the [ 13 C 6 , 2 H 7 ]glucose formulations, [7,13,14,19,20,23] a methodological investigation of the potential effects of Gd 3 + on the solid-state polarization of [ 13 C 6 , 2 H 7 ]glucose at 3.35 T has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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The Effect of Gadolinium Doping in [¹³C₆,²H₇]Glucose Formulations on ¹³C Dynamic Nuclear Polarization at 3.35 T

et al. 2020

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The promise of hyperpolarized glucose as a non-radioactive imaging agent capable of reporting on multiple metabolic routes has led to recent advances in its dissolution-DNP (dDNP) driven polarization using UV-light induced radicals and trityl radicals at high field (6.7 T) and 1.1 K. However, most preclinical dDNP polarizers operate at the field of 3.35 T and 1.4-1.5 K. Minute amounts of Gd 3 + complexes have shown large improvements in solid-state polarization, which can be translated to improved hyperpolarization in solution. However, this Gd 3 + effect seems to depend on magnetic field strength, metal ion concentration, and sample formulation. The effect of varying Gd 3 + concentrations at 3.35 T has been described for 13 Clabeled pyruvic acid and acetate. However, it has not been studied for other compounds at this field. The results presented here suggest that Gd 3 + doping can lead to various concentration and temperature dependent effects on the polarization of [ 13 C 6 , 2 H 7 ]glucose, not necessarily similar to the effects observed in pyruvic acid or acetate in size or direction. The maximal polarization for [ 13 C 6 , 2 H 7 ]glucose appears to be at a Gd 3 + concentration of 2 mM, when irradiating for more than 2 h at the negative maximum of the DNP intensity profile. Surprisingly, for shorter irradiation times, higher polarization levels were determined at 1.50 K compared to 1.45 K, at a [Gd 3 + ] = 1.3 mM. This was explained by the build-up time constant and maximum at these temperatures.[a] Dr.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Effect of Gadolinium Doping in [¹³C₆,²H₇]Glucose Formulations on ¹³C Dynamic Nuclear Polarization at 3.35 T

et al. 2020

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Production of highly polarized [1‐¹³C]acetate by rapid decarboxylation of [2‐¹³C]pyruvate – application to hyperpolarized cardiac spectroscopy and imaging

Steinhauser

Wespi

Kwiatkowski

et al. 2019

Magnetic Resonance in Med

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Purpose:The objective of the present work was to develop and implement an efficient approach to hyperpolarize [1-13 C]acetate and apply it to in vivo cardiac spectroscopy and imaging. Methods: Rapid hydrogen peroxide induced decarboxylation was used to convert hyperpolarized [2-13 C]pyruvate into highly polarized [1-13 C]acetate employing an additional step following rapid dissolution of [2-13 C]pyruvate in a home-built multisample dissolution dynamic nuclear polarization system. Phantom dissolution experiments were conducted to determine optimal parameters of the decarboxylation reaction, retaining polarization and T 1 of [1-13 C]acetate. In vivo feasibility of detecting [1-13 C]acetate metabolism is demonstrated using slice-selective spectroscopy and multi-echo imaging of [1-13 C]acetate and [1-13 C]acetylcarnitine in the healthy rat heart. Results: The first in vivo signal was observed ~23 s after dissolution. At the corresponding time point in the phantom experiments, 97.9 ± 0.4% of [2-13 C]pyruvate were converted into [1-13 C]acetate by the decarboxylation reaction. T 1 and polarization of [1-13 C]acetate was determined to be 29.7 ± 1.9% and a 47.7 ± 0.5 s.Polarization levels of [2-13 C]pyruvate and [1-13 C]acetate were not significantly different after transfer to the scanner. In vivo, [1-13 C]acetate and [1-13 C]acetylcarnitine could be detected using spectroscopy and imaging. Conclusion: Decarboxylation of hyperpolarized [2-13 C]pyruvate enables the efficient production of highly polarized [1-13 C]acetate that is applicable to study shortchain fatty acid metabolism in the in vivo heart. K E Y W O R D Sacetate, cardiac metabolism, DNP, dynamic nuclear polarisation, hyperpolarized 13C | INTRODUCTIONAdenosine triphosphate (ATP), the energy currency of the eukaryotic cell, is derived via 2 main pathways-mitochondrial metabolism, accounting for 95% of the generated ATP and glycolytic energy generation. Among various substrates, fatty acids and carbohydrates constitute the main sources of energy with fatty acids accounting for 70-90% of the energy supply ORCID Jonas Steinhauserhttps://orcid.org/0000-0003-3916-1285Patrick Wespi https://orcid.org/0000-0003-4309-445XGrzegorz Kwiatkowski

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Detection of myocardial medium‐chain fatty acid oxidation and tricarboxylic acid cycle activity with hyperpolarized [1–¹³C]octanoate

et al. 2020

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Under normal conditions, the heart mainly relies on fatty acid oxidation to meet its energy needs. Changes in myocardial fuel preference are noted in the diseased and failing heart. The magnetic resonance signal enhancement provided by spin hyperpolarization allows the metabolism of substrates labeled with carbon-13 to be followed in real time in vivo. Although the low water solubility of long-chain fatty acids abrogates their hyperpolarization by dissolution dynamic nuclear polarization, mediumchain fatty acids have sufficient solubility to be efficiently polarized and dissolved. In this study, we investigated the applicability of hyperpolarized [1-13 C]octanoate to measure myocardial medium-chain fatty acid metabolism in vivo. Scanning rats infused with a bolus of hyperpolarized [1-13 C]octanoate, the primary metabolite observed in the heart was identified as [1-13 C]acetylcarnitine. Additionally, [5-13 C] glutamate and [5-13 C]citrate could be respectively resolved in seven and five of 31 experiments, demonstrating the incorporation of oxidation products of octanoate into the tricarboxylic acid cycle. A variable drop in blood pressure was observed immediately following the bolus injection, and this drop correlated with a decrease in normalized acetylcarnitine signal (acetylcarnitine/octanoate). Increasing the delay before infusion moderated the decrease in blood pressure, which was attributed to the presence of residual gas bubbles in the octanoate solution. No significant difference in normalized acetylcarnitine signal was apparent between fed and 12-hour fasted rats. Compared with a solution in buffer, the longitudinal relaxation of [1-13 C] octanoate was accelerated~3-fold in blood and by the addition of serum albumin.These results demonstrate the potential of hyperpolarized [1-13 C]octanoate to probe myocardial medium-chain fatty acid metabolism as well as some of the limitations that may accompany its use. K E Y W O R D S13 C-MRS, beta-oxidation, cardiac, dissolution dynamic nuclear polarization, hyperpolarization, medium-chain triglyceride, serum albumin Abbreviations: BSA, bovine serum albumin; DNP, dynamic nuclear polarization; FFA, free fatty acid; IBP, invasive blood pressure; LCAD, long-chain acyl-CoA dehydrogenase; M/SCHAD, medium-and short-chain L-3-hydroxyacyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; MKAT, medium-chain 3-ketoacyl-CoA thiolase; PBS, phosphate buffered saline;RPP, rate-pressure product; SCAD, short-chain acyl-CoA dehydrogenase; TCA, tricarboxylic acid; VLCAD, very long-chain acyl-CoA dehydrogenase.

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Biomolecular imaging of 13C-butyrate with dissolution-DNP: Polarization enhancement and formulation for in vivo studies

Cited by 9 publications

References 60 publications

The Effect of Gadolinium Doping in [¹³C₆,²H₇]Glucose Formulations on ¹³C Dynamic Nuclear Polarization at 3.35 T

The Effect of Gadolinium Doping in [¹³C₆,²H₇]Glucose Formulations on ¹³C Dynamic Nuclear Polarization at 3.35 T

Production of highly polarized [1‐¹³C]acetate by rapid decarboxylation of [2‐¹³C]pyruvate – application to hyperpolarized cardiac spectroscopy and imaging

Detection of myocardial medium‐chain fatty acid oxidation and tricarboxylic acid cycle activity with hyperpolarized [1–¹³C]octanoate

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Biomolecular imaging of 13C-butyrate with dissolution-DNP: Polarization enhancement and formulation for in vivo studies

Cited by 9 publications

References 60 publications

The Effect of Gadolinium Doping in [13C6,2H7]Glucose Formulations on 13C Dynamic Nuclear Polarization at 3.35 T

The Effect of Gadolinium Doping in [13C6,2H7]Glucose Formulations on 13C Dynamic Nuclear Polarization at 3.35 T

Production of highly polarized [1‐13C]acetate by rapid decarboxylation of [2‐13C]pyruvate – application to hyperpolarized cardiac spectroscopy and imaging

Detection of myocardial medium‐chain fatty acid oxidation and tricarboxylic acid cycle activity with hyperpolarized [1–13C]octanoate

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The Effect of Gadolinium Doping in [¹³C₆,²H₇]Glucose Formulations on ¹³C Dynamic Nuclear Polarization at 3.35 T

The Effect of Gadolinium Doping in [¹³C₆,²H₇]Glucose Formulations on ¹³C Dynamic Nuclear Polarization at 3.35 T

Production of highly polarized [1‐¹³C]acetate by rapid decarboxylation of [2‐¹³C]pyruvate – application to hyperpolarized cardiac spectroscopy and imaging

Detection of myocardial medium‐chain fatty acid oxidation and tricarboxylic acid cycle activity with hyperpolarized [1–¹³C]octanoate