High-yield reactor production of terbium-161 using thin-layer gadolinium-160 targets, simplified chloride based separation and radiolabeling of DOTA based ligands

Abstract

Background

Terbium-161 (¹⁶¹ Tb) is an emerging therapeutic radionuclide combining β⁻ emission with a high yield of Auger electrons and conversion electrons, enabling enhanced localized dose deposition. However, its widespread clinical adoption is limited by inefficient target utilization and multistep post-irradiation processing. This study aimed to develop a simplified high-yield production and direct chloride-based purification workflow for clinical-grade terbium-161 using thin-layer enriched gadolinium-160 targets under limited-resource reactor conditions. Terbium-161 was produced by neutron irradiation of enriched Gadolinium-160 targets fabricated as conventional oxide powder and novel thin-layer chloride films at a thermal neutron flux of 1.5 × 10¹⁴ n cm⁻² s⁻¹ for 24 h in Pakistan Atomic Research Reactor-1 (PARR-I). Post-irradiation separation of terbium was carried out using LN resin employing HCl and HNO₃ media, and compared with α-hydroxyisobutyric acid (α-HIBA) cation-exchange chromatography. Radionuclidic purity was assessed by HPGe γ spectrometry, while radiochemical purity and labeling efficiency with DOTA conjugated Peptides were evaluated using ITLC and HPLC.

Results

Thin-layer targets significantly enhanced neutron utilization, compared to oxide targets due to reduced self-shielding of target. The specific activities achieved across three production batches (34.25–79.01 MBq/mg) demonstrated an approximately 2.3-fold higher specific activity with ¹⁶⁰GdCl₃ layered targets than bulk Gd₂O₃ targets. LN–HCl separation provided superior recovery (91.4%) and enabled direct formulation of [¹⁶¹ Tb]TbCl₃, eliminating post-processing steps required in nitrate systems and cation exchange with α -HIBA. Radionuclidic purity exceeded 99.99%, with minimal Terbium-160 impurity and Radiolabeling yields with DOTA-conjugated peptides exceeded 95.0%.

Conclusion

Target geometry plays a critical role in reactor-based radionuclide production. The integrated thin-layer target and chloride-based separation workflow provides a simplified, high-yield approach for production of terbium-161, enables efficient radiolabeling with DOTA-based ligands. These findings provide a foundation for further analytical qualification required for preclinical and clinical translations.

Graphical abstract