Jonathan R Birchall, Pascal Wodtke, Ashley Grimmer, Esben S S Hansen, Lotte B Bertelsen, Nikolaj Bøgh, Marta Wylot, Maria J Zamora-Morales, Otso Arponen, Ines Horvat-Menih, Elizabeth C Latimer, Fung Tan, Evita Pappa, Johann Graggaber, Joseph Cheriyan, Kelly Holmes, Matthew J Locke, Helen Sladen, Joan Boren, Mikko I Kettunen, Anita Chhabra, Ian B Wilkinson, Christoffer Laustsen, Kevin Brindle, Mary A McLean, Ferdia A Gallagher
{"title":"A pathway toward clinical translation of hyperpolarized [1,4-<sup>13</sup>C<sub>2</sub>,2,3-d<sub>2</sub>]fumarate as an imaging biomarker for early cellular necrosis in vivo.","authors":"Jonathan R Birchall, Pascal Wodtke, Ashley Grimmer, Esben S S Hansen, Lotte B Bertelsen, Nikolaj Bøgh, Marta Wylot, Maria J Zamora-Morales, Otso Arponen, Ines Horvat-Menih, Elizabeth C Latimer, Fung Tan, Evita Pappa, Johann Graggaber, Joseph Cheriyan, Kelly Holmes, Matthew J Locke, Helen Sladen, Joan Boren, Mikko I Kettunen, Anita Chhabra, Ian B Wilkinson, Christoffer Laustsen, Kevin Brindle, Mary A McLean, Ferdia A Gallagher","doi":"10.1002/mrm.30519","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>The detection of hyperpolarized carbon-13 (HP <sup>13</sup>C)-fumarate conversion to <sup>13</sup>C-malate using <sup>13</sup>C-MRSI is a biomarker for early detection of cellular necrosis. Here, we describe the translation of HP <sup>13</sup>C-fumarate as a novel human imaging agent, including the evaluation of biocompatibility and scaling up of the hyperpolarization methods for clinical use.</p><p><strong>Methods: </strong>Preclinical biological validation was undertaken in fumarate hydratase-deficient murine tumor models and controls. Safety and biocompatibility of <sup>13</sup>C-fumarate was assessed in healthy rats (N = 18) and in healthy human volunteers (N = 9). The dissolution dynamic nuclear polarization process for human doses of HP <sup>13</sup>C-fumarate was optimized in phantoms. Finally, 2D <sup>13</sup>C-MRSI following injection of HP <sup>13</sup>C-fumarate was performed in an ischemia-reperfusion porcine kidney model (N = 6).</p><p><strong>Results: </strong>Fumarate-to-malate conversion was reduced by 42%-71% in the knockdown murine tumor model compared to wildtype tumors. Twice-daily injection of <sup>13</sup>C-fumarate in healthy rats at the maximum evaluated dose (120 mg/kg/day) showed no significant persistent blood or tissue effects. Healthy human volunteers injected at the maximum dose (3.84 mg/kg) and injection rate (5 mL/s) showed no statistically significant changes in vital signs or blood measurements 1 h post-injection. Spectroscopic evidence of fumarate-to-malate conversion was observed in the ischemic porcine kidney (0.96 mg/kg).</p><p><strong>Conclusion: </strong>HP <sup>13</sup>C-fumarate has shown promise as a novel and safe hyperpolarized agent for monitoring cellular necrosis. This work provides the basis for future imaging of HP <sup>13</sup>C-fumarate metabolism in humans.</p>","PeriodicalId":18065,"journal":{"name":"Magnetic Resonance in Medicine","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Magnetic Resonance in Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/mrm.30519","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: The detection of hyperpolarized carbon-13 (HP 13C)-fumarate conversion to 13C-malate using 13C-MRSI is a biomarker for early detection of cellular necrosis. Here, we describe the translation of HP 13C-fumarate as a novel human imaging agent, including the evaluation of biocompatibility and scaling up of the hyperpolarization methods for clinical use.
Methods: Preclinical biological validation was undertaken in fumarate hydratase-deficient murine tumor models and controls. Safety and biocompatibility of 13C-fumarate was assessed in healthy rats (N = 18) and in healthy human volunteers (N = 9). The dissolution dynamic nuclear polarization process for human doses of HP 13C-fumarate was optimized in phantoms. Finally, 2D 13C-MRSI following injection of HP 13C-fumarate was performed in an ischemia-reperfusion porcine kidney model (N = 6).
Results: Fumarate-to-malate conversion was reduced by 42%-71% in the knockdown murine tumor model compared to wildtype tumors. Twice-daily injection of 13C-fumarate in healthy rats at the maximum evaluated dose (120 mg/kg/day) showed no significant persistent blood or tissue effects. Healthy human volunteers injected at the maximum dose (3.84 mg/kg) and injection rate (5 mL/s) showed no statistically significant changes in vital signs or blood measurements 1 h post-injection. Spectroscopic evidence of fumarate-to-malate conversion was observed in the ischemic porcine kidney (0.96 mg/kg).
Conclusion: HP 13C-fumarate has shown promise as a novel and safe hyperpolarized agent for monitoring cellular necrosis. This work provides the basis for future imaging of HP 13C-fumarate metabolism in humans.
期刊介绍：
Magnetic Resonance in Medicine (Magn Reson Med) is an international journal devoted to the publication of original investigations concerned with all aspects of the development and use of nuclear magnetic resonance and electron paramagnetic resonance techniques for medical applications. Reports of original investigations in the areas of mathematics, computing, engineering, physics, biophysics, chemistry, biochemistry, and physiology directly relevant to magnetic resonance will be accepted, as well as methodology-oriented clinical studies.
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