Tb-labeled bisphosphonates as potential agents for bone-targeted radiotherapy

Abstract

Radiopharmaceutical therapy using bone-targeting agents labeled with β-emitting radionuclides has proven effective for pain palliation and disease management. This study aimed to develop 161Tb-labeled bisphosphonates with high radiolabeling yield, in vitro stability, and appropriate biodistribution. Etidronate and zoledronate were radiolabeled with 161Tb at room temperature (pH 7), whereas the DOTAconjugated bisphosphonate BPAMD was labeled with 161Tb under mild heating conditions (95 °C, 30 min). Stability studies were performed under physiological conditions. In vitro hydroxyapatite binding assays were conducted to evaluate mineral affinity. Biodistribution studies were conducted in healthy Wistar rats following intravenous administration, and radioactivity in excised organs was measured by gamma counting and expressed as percentage of the injected dose (%ID). All radiocomplexes were obtained with radiochemical yields exceeding 98%, as confirmed by ITLC method. The compounds exhibited excellent stability in saline (>95%) and human serum (>94%) over 48 h. Hydroxyapatite binding studies demonstrated strong mineral affinity with high binding (>98%). Biodistribution studies revealed rapid and pronounced skeletal uptake, with more than 60% of the injected activity localized in bone within 2 hours post-injection. Uptake in soft-tissues and non-target organs was low and declined rapidly, indicating favorable pharmacokinetics and prolonged bone retention. All bisphosphonates showed excellent in vitro stability and strong bone affinity with high skeletal uptake and low non-target accumulation. These results support further evaluation of 161Tb-labeled diphosphonates in tumor-bearing models and comparative studies with established 177Lu analogs, positioning them as strong candidates for bone-targeted radionuclide therapy.