Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized <sup>13</sup>C‐Labeled Molecular Probe

Nishihara, Tatsuya; Yoshihara, Hikari A.I.; Nonaka, Hiroshi; Takakusagi, Yoichi; Hyodo, Fuminori; Ichikawa, Kazuhiro; Can, Emine; Bastiaansen, Jessica; Takado, Yuhei; Comment, Arnaud; Sando, Shinsuke

doi:10.1002/ange.201603731

Cited by 16 publications

(14 citation statements)

References 36 publications

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“…Hyperpolarization methods overcome the relatively low sensitivity of MRS, and by combining dissolution dynamic nuclear polarization (DNP) and 13 C MRS imaging, in vivo metabolism can be probed in real time . Hyperpolarized 13 C MR has already been used extensively in a wide range of preclinical models, in which it was shown to be sensitive to variations in key metabolic pathways . The technique has recently been translated to studies investigating prostate cancer and heart disease in human subjects .…”

Section: Introductionmentioning

confidence: 99%

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo‐induced nonpersistent radicals

Bastiaansen

Yoshihara

Capozzi

et al. 2018

Magnetic Resonance in Med

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Purpose To probe the cardiac metabolism of carbohydrates and short chain fatty acids simultaneously in vivo following the injection of a hyperpolarized 13C-labeled substrate mixture prepared using photo-induced non-persistent radicals. Methods Droplets of mixed [1-13C]pyruvic and [1-13C]butyric acids were frozen into glassy beads in liquid nitrogen. Ethanol addition was investigated as a means to increase the polarization level. The beads were irradiated with ultraviolet (UV) light and the radical concentration was measured by ESR spectroscopy. Following dynamic nuclear polarization (DNP) in a 7T polarizer, the beads were dissolved, and the radical-free hyperpolarized solution was rapidly transferred into an injection pump located inside a 9.4T scanner. The hyperpolarized solution was injected in healthy rats to measure cardiac metabolism in vivo. Results UV-irradiation created non-persistent radicals in a mixture containing 13C-labeled pyruvic and butyric acids and enabled the hyperpolarization of both substrates by DNP. Ethanol addition increased the radical concentration from 16 to 26 mM. Liquid-state 13C polarization was 3% inside the pump at the time of injection, and increased to 5% by addition of ethanol to the substrate mixture prior to UV irradiation. In the rat heart, the in vivo 13C signals from lactate, alanine, bicarbonate and acetylcarnitine were detected following the metabolism of the injected substrate mixture. Conclusion Co-polarization of two 13C-labeled substrates and the detection of their myocardial metabolism in vivo was achieved without using persistent radicals. The absence of radicals in the solution containing the hyperpolarized 13C-substrates may simplify the translation to clinical use because no filtration is required prior to injection.

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Section: Introductionmentioning

confidence: 99%

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo‐induced nonpersistent radicals

Bastiaansen

Yoshihara

Capozzi

et al. 2018

Magnetic Resonance in Med

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“…The high sensitivity that can be achieved with hyperpolarized molecular sensors has led to the application of such systems for in vivo enzymatic analysis2345. A representative example is hyperpolarized [1- 13 C]pyruvate, the use of which is being explored as a diagnostic tool for noninvasive analysis of tumor status3.…”

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confidence: 99%

Design of a 15N Molecular Unit to Achieve Long Retention of Hyperpolarized Spin State

Nonaka

Hirano

Imakura

et al. 2017

Sci Rep

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Nuclear hyperpolarization is a phenomenon that can be used to improve the sensitivity of magnetic resonance molecular sensors. However, such sensors typically suffer from short hyperpolarization lifetime. Herein we report that [15N, D14]trimethylphenylammonium (TMPA) has a remarkably long spin–lattice relaxation time (1128 s, 14.1 T, 30 °C, D2O) on its 15N nuclei and achieves a long retention of the hyperpolarized state. [15N, D14]TMPA-based hyperpolarized sensor for carboxylesterase allowed the highly sensitive analysis of enzymatic reaction by 15N NMR for over 40 min in phophate-buffered saline (H2O, pH 7.4, 37 °C).

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“…Despite the limitations imposed by the requirements for high solubility, long polarization lifetime, and fast metabolism, an impressive array of 13 C-labeled molecules have been hyperpolarized and studied in vivo (reviewed in Keshari and Wilson (2014)). Some recent additions to this growing list include g-glutamyl-[1-13 C]glycine, which is cleaved by a cell surface enzyme, g-glutamyl transpeptidase (GGT), to yield free [1-13 C]glycine (Nishihara et al, 2016). GGT is overexpressed in several different tumor types, including those arising in tissues that do not normally express the enzyme, such as ovarian adenocarcinoma, and it therefore has the potential to act as a tumor biomarker.…”

Section: Imaging the Mutational Status Of Isocitrate Dehydrogenasementioning

confidence: 99%

Emerging Technologies to Image Tissue Metabolism

et al. 2019

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Due to the implication of altered metabolism in a large spectrum of tissue function and disease, assessment of metabolic processes becomes essential in managing health. In this regard, imaging can play a critical role in allowing observation of biochemical and physiological processes. Nuclear imaging methods, in particular positron emission tomography, have been widely employed for imaging metabolism but are mainly limited by the use of ionizing radiation and the sensing of only one parameter at each scanning session. Observations in healthy individuals or longitudinal studies of disease could markedly benefit from non-ionizing, multi-parameter imaging methods. We therefore focus this review on progress with the non-ionizing radiation methods of MRI, hyperpolarized magnetic resonance and magnetic resonance spectroscopy, chemical exchange saturation transfer, and emerging optoacoustic (photoacoustic) imaging. We also briefly discuss the role of nuclear and optical imaging methods for research and clinical protocols.

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Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized ¹³C‐Labeled Molecular Probe

Cited by 16 publications

References 36 publications

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo‐induced nonpersistent radicals

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo‐induced nonpersistent radicals

Design of a 15N Molecular Unit to Achieve Long Retention of Hyperpolarized Spin State

Emerging Technologies to Image Tissue Metabolism

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Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized 13C‐Labeled Molecular Probe

Cited by 16 publications

References 36 publications

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo‐induced nonpersistent radicals

Probing cardiac metabolism by hyperpolarized 13C MR using an exclusively endogenous substrate mixture and photo‐induced nonpersistent radicals

Design of a 15N Molecular Unit to Achieve Long Retention of Hyperpolarized Spin State

Emerging Technologies to Image Tissue Metabolism

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Direct Monitoring of γ‐Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized ¹³C‐Labeled Molecular Probe