Prostate-specific membrane antigen (PSMA) is a well-established molecular target for the diagnosis and treatment of prostate cancer due to its high and consistent overexpression in advanced, recurrent, and metastatic disease. PSMA-targeted radioligand therapy has demonstrated significant clinical benefit, particularly using ß-emitting radionuclides such as 177 Lu. However, the development of alternative therapeutic radionuclides with improved radiophysical characteristics remains of high interest. Terbium-161 (¹⁶¹Tb) has recently emerged as a promising therapeutic radionuclide, combining medium-energy ß emissions with a high yield of conversion and Auger electrons. This emission profile may enhance the absorbed radiation dose at the cellular and subcellular levels, particularly in small tumor lesions and micrometastatic disease. These favorable properties suggest that ¹⁶¹Tb could offer potential advantages over conventional therapeutic radionuclides when stably incorporated into PSMA-targeting ligands. The objective of this study was to evaluate and optimize the radiolabeling of a PSMA-targeting ligand with ¹⁶¹Tb and to assess the feasibility of producing a stable, high-purity radiopharmaceutical suitable for further preclinical investigation. Terbium-161 was supplied in HCl solution (Terthera or ISOTOPIA) and PSMA-617 was obtained from CMR. Radiolabeling was performed using either 4 M acetate buffer (pH 4.6) or sodium ascorbate buffer (prepared with 20 mg of ascorbic acid and 80 mg of sodium ascorbate per mL). The reaction mixture was heated in a dry heating block at 95°C for up to 30 minutes, using PSMA-617 molar ratios of up to 40 nmoL/GBq. Final formulation was achieved by dilution of the radiolabeled product to a total volume of 10 mL with 0.9% NaCl, followed by terminal sterilization through a 0.2 µm filter. Quality control was performed using high-performance liquid chromatography (HPLC) and instant thin-layer chromatography (iTLC). HPLC analysis was conducted on a 150 × 4.6 mm reversed-phase C18 column (M&N) using A) 0.1% TFA in water and B) 0.1% TFA in acetonitrile as mobile phases at a flow rate of 1 mL/min. The gradient consisted of 20% B at 0 min, increasing from 20% to 95% B over 15 minutes, followed by 95% B from 15 to 20 minutes, using UV and gamma detection. iTLC-SG (Agilent) analysis was performed using NH3:EtOH:H2O (0.2:1:2) as the mobile phase. Optimal radiolabeling conditions were achieved using sodium ascorbate buffer with heating at 95°C for 25 minutes. Under these optimized conditions, the PSMA-617 to ¹6¹Tb molar ratio was determined to be 20 nmoL/GBq. A radiochemical purity of 99.6 ± 0.4% was obtained and remained above 95% for at least 5 days. No post-labeling purification was required, indicating a robust and efficient radiolabeling procedure. Radiolabeling optimization was successfully achieved, with the best performance obtained under conditions similar to those commonly employed for ¹77Lu labeling using sodium ascorbate buffer. The high radiochemical purity, extended stability, and optimized molar ratio support the reliable preparation of ¹⁶¹TbTb-PSMA-617 with suitable characteristics for preclinical studies. These results highlight the potential of ¹⁶¹Tb as a promising radionuclide for PSMA-targeted radionuclide therapy.
Giglio et al. (Sun,) studied this question.