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

[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.

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.

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.