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Background <p>[<sup>211</sup>At]PSMA-5 is a novel α-emitting therapeutic agent designed to target prostate-specific membrane antigen (PSMA), which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). Unlike β-emitting radioligands, [<sup>211</sup>At]PSMA-5 delivers highly localized cytotoxicity while minimizing damage to surrounding normal tissues. To enable clinical application, the objective of this study is to scale up the lab-scale synthesis to an automated manufacturing process that ensures high reproducibility and sufficient radioactivity for human administration.</p> Results <p>We developed and optimized a scalable automated synthesis method for [<sup>211</sup>At]PSMA-5 using the COSMiC-Mini VTRSC2 automated synthesizer. Optimization involved evaluating the recovery efficiency of <sup>211</sup>At from the cold trap and reaction conditions, followed by automated synthesis under investigational new drug Good Manufacturing Practice conditions. Quality control of the synthesized [<sup>211</sup>At]PSMA-5 included assessment of radiochemical purity, radionuclide identity, impurity profile and sterility. Optimization with sodium hydrogen carbonate (7%) achieved over 90% recovery of <sup>211</sup>At from the cold trap, and labeling rate of up to 93% were obtained using glass reaction vessels with stirring at 95&#xa0;°C. Three automated syntheses were conducted using irradiated Bi targets containing <sup>211</sup>At produced at two different facilities. Consistent radiochemical yield (approximately 30%) and high radiochemical purity (96 ± 1%) were achieved. Additional quality control confirmed the absence of impurities such as <sup>210</sup>At, Bi residues, and iodide, as well as sterility and chemical stability suitable for intravenous administration.</p> Conclusions <p>This study successfully established an automated, scalable production process for [<sup>211</sup>At]PSMA-5 that meets clinical-grade quality requirements, enabling stable and reproducible manufacturing for investigator-initiated clinical trials in mCRPC. Equivalent radiochemical yields and consistent quality were obtained using irradiated Bi targets from two cyclotron facilities (RCNP and RIKEN), demonstrating site-independent robustness. This flexible system ensures a reliable supply and resilience to unexpected cyclotron downtime, representing a significant step toward clinical application of <sup>211</sup>At-based PSMA-targeted alpha therapy.</p>

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Scale-up production of [211At]PSMA-5 using automated synthesizer for Investigator-Initiated clinical trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月27日

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  • Sadahiro Naka,
  • Tadashi Watabe,
  • Yoshifumi Shirakami,
  • Kazuhiro Ooe,
  • Kenta Kurimoto,
  • Toshihiro Sakai,
  • Atsushi Toyoshima,
  • Masashi Murakami,
  • Yukiyoshi Kon,
  • Hiromitsu Haba,
  • Jens Cardinale,
  • Frederik L. Giesel,
  • Kayako Isohashi,
  • Noriyuki Tomiyama

摘要

Background

[211At]PSMA-5 is a novel α-emitting therapeutic agent designed to target prostate-specific membrane antigen (PSMA), which is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). Unlike β-emitting radioligands, [211At]PSMA-5 delivers highly localized cytotoxicity while minimizing damage to surrounding normal tissues. To enable clinical application, the objective of this study is to scale up the lab-scale synthesis to an automated manufacturing process that ensures high reproducibility and sufficient radioactivity for human administration.

Results

We developed and optimized a scalable automated synthesis method for [211At]PSMA-5 using the COSMiC-Mini VTRSC2 automated synthesizer. Optimization involved evaluating the recovery efficiency of 211At from the cold trap and reaction conditions, followed by automated synthesis under investigational new drug Good Manufacturing Practice conditions. Quality control of the synthesized [211At]PSMA-5 included assessment of radiochemical purity, radionuclide identity, impurity profile and sterility. Optimization with sodium hydrogen carbonate (7%) achieved over 90% recovery of 211At from the cold trap, and labeling rate of up to 93% were obtained using glass reaction vessels with stirring at 95 °C. Three automated syntheses were conducted using irradiated Bi targets containing 211At produced at two different facilities. Consistent radiochemical yield (approximately 30%) and high radiochemical purity (96 ± 1%) were achieved. Additional quality control confirmed the absence of impurities such as 210At, Bi residues, and iodide, as well as sterility and chemical stability suitable for intravenous administration.

Conclusions

This study successfully established an automated, scalable production process for [211At]PSMA-5 that meets clinical-grade quality requirements, enabling stable and reproducible manufacturing for investigator-initiated clinical trials in mCRPC. Equivalent radiochemical yields and consistent quality were obtained using irradiated Bi targets from two cyclotron facilities (RCNP and RIKEN), demonstrating site-independent robustness. This flexible system ensures a reliable supply and resilience to unexpected cyclotron downtime, representing a significant step toward clinical application of 211At-based PSMA-targeted alpha therapy.