Optimization of reaction conditions and process automation for 99mTcTc-PSMA-I&S preparation on a GAIA® synthesizer

Background Radioguided surgery (RGS) using PSMA radioligands emerged as a valuable approach for the detection of metastatic lymph nodes in prostate cancer. 99 m TcTc-PSMA-I&S is specifically designed for combined imaging and RGS, however, its clinical implementation as an experimental radiopharmaceutical remains limited by heterogeneous radiolabeling procedures, particularly in automated preparation settings. Objectives To optimize the preparation conditions of 99 m TcTc-PSMA-I&S and develop an automated synthesis protocol. Methods A systematic study of the PSMA-I&S radiolabeling conditions with 99 m Tc was conducted using manual preparations. Key parameters including buffer type and concentration, transfer ligand, antioxidant compound, precursor amount, and heating time were evaluated based on radiochemical purity (RCP) assessed by radio-HPLC. Optimized conditions were subsequently transposed to a fully-automated synthesis on a GAIA® module, following a workflow based on 68 Ga radiopharmaceuticals. Three test batches were produced and subjected to extensive quality controls, including RCP, radiochemical yield (RCY) and stability. Results Manual optimization identified sodium formate buffer (1.5 M, pH 8.5), stannous chloride as the sole reducing agent, and 95 °C heating for 5 min as optimal conditions, yielding RCP values ≥ 98% without requiring any transfer ligand or antioxidant. These conditions were successfully implemented on the synthesizer. Automated production of 99 m TcTc-PSMA-I&S (n = 3) was achieved within 24.12 ± 0.20 min, starting from 3.31 ± 0.18 GBq of 99 m Tc, with RCY of 72.3 ± 6.7% and RCP of 95.27 ± 0.21%. All batches remained stable over 6 h, maintaining RCP > 95%. Conclusion This work establishes a fast, simplified and fully automated radiolabeling process for 99 m TcTc-PSMA-I&S. The proposed methodology supports GMP-compliant production and would facilitate the broader implementation of PSMA-targeted RGS.