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Background <p>Mercury-197m (<sup>197m</sup>Hg, t<sub>1/2</sub> = 23.8&#xa0;h) and mercury-197g (<sup>197g</sup>Hg, t<sub>1/2</sub> = 64.14&#xa0;h) possess favorable nuclear properties for imaging and targeted therapy, but the development of suitable chelators for mercury-based radiopharmaceuticals remains underexplored. Additionally, accurate imaging and quantification of mercury isotopes, particularly in dual-isotope formats, require tools that account for their complex decay schemes. Phantom imaging studies are essential for validating spatial resolution, quantitative accuracy, and isotope-specific calibration prior to in vivo application. In this study, we investigated the commercially available ligand H<sub>4</sub>Tetrathiol for chelation of [<sup>197m/g</sup>Hg]Hg<sup>2+</sup> and developed a robust imaging and quantification pipeline to support the use of these nuclear isomers in preclinical imaging.</p> Results <p>Radiolabeling of H<sub>4</sub>Tetrathiol yielded exceptionally efficient complexation, achieving the lowest ligand-to-metal ratio reported for radio-mercury. The resulting [<sup>197m/g</sup>Hg]Hg<sup>2+</sup>-complex demonstrated high in vitro stability in the presence of serum proteins, glutathione, and competing biologically relevant metal ions, though it exhibited kinetic lability when challenged with excess HgCl₂. In vivo biodistribution studies in mice showed a distinct pharmacokinetic profile from unchelated [<sup>197m/g</sup>Hg]HgCl₂, suggesting in vivo complex stability. Phantom imaging studies with a high sensitivity collimator demonstrated submillimeter resolution (≥ 1.1&#xa0;mm) for both <sup>197g</sup>Hg and <sup>197m</sup>Hg, with decay behavior consistent with known half-lives. To facilitate accurate quantification, we developed <i>HgQuant</i>, a Python-based tool for isotope-specific calibration, Bateman decay correction, and automated dual-isotope analysis. This tool enabled reproducible, time-resolved quantification in both phantom and in vivo settings.</p> Conclusions <p>These results establish Tetrathiol as a promising scaffold for mercury-based theranostics, offering efficient radiolabeling and in vivo stability. The integration of high-resolution imaging and <i>HgQuant</i>-based quantification of each isomer establishes a comprehensive framework for advancing [<sup>197m/g</sup>Hg]Hg radiopharmaceutical development.</p>

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Quantitative dual-isotope preclinical SPECT/CT imaging and biodistribution of the mercury-197m/g theranostic pair with [197m/gHg]HgCl2 and a [197m/gHg]Hg-tetrathiol complex as a platform for radiopharmaceutical development

  • 期刊论文

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  • 发表日期：

    2025年10月14日

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  • Parmissa Randhawa,
  • Cristina Rodríguez-Rodríguez,
  • Helena Koniar,
  • Patrick R. W. J. Davey,
  • Shaohuang Chen,
  • Valery Radchenko,
  • Caterina F. Ramogida

摘要

Background

Mercury-197m (197mHg, t1/2 = 23.8 h) and mercury-197g (197gHg, t1/2 = 64.14 h) possess favorable nuclear properties for imaging and targeted therapy, but the development of suitable chelators for mercury-based radiopharmaceuticals remains underexplored. Additionally, accurate imaging and quantification of mercury isotopes, particularly in dual-isotope formats, require tools that account for their complex decay schemes. Phantom imaging studies are essential for validating spatial resolution, quantitative accuracy, and isotope-specific calibration prior to in vivo application. In this study, we investigated the commercially available ligand H4Tetrathiol for chelation of [197m/gHg]Hg2+ and developed a robust imaging and quantification pipeline to support the use of these nuclear isomers in preclinical imaging.

Results

Radiolabeling of H4Tetrathiol yielded exceptionally efficient complexation, achieving the lowest ligand-to-metal ratio reported for radio-mercury. The resulting [197m/gHg]Hg2+-complex demonstrated high in vitro stability in the presence of serum proteins, glutathione, and competing biologically relevant metal ions, though it exhibited kinetic lability when challenged with excess HgCl₂. In vivo biodistribution studies in mice showed a distinct pharmacokinetic profile from unchelated [197m/gHg]HgCl₂, suggesting in vivo complex stability. Phantom imaging studies with a high sensitivity collimator demonstrated submillimeter resolution (≥ 1.1 mm) for both 197gHg and 197mHg, with decay behavior consistent with known half-lives. To facilitate accurate quantification, we developed HgQuant, a Python-based tool for isotope-specific calibration, Bateman decay correction, and automated dual-isotope analysis. This tool enabled reproducible, time-resolved quantification in both phantom and in vivo settings.

Conclusions

These results establish Tetrathiol as a promising scaffold for mercury-based theranostics, offering efficient radiolabeling and in vivo stability. The integration of high-resolution imaging and HgQuant-based quantification of each isomer establishes a comprehensive framework for advancing [197m/gHg]Hg radiopharmaceutical development.