Evaluation of 161Tb-Labeled Diphosphonates as Potential Bone-Targeting Agents

TL;DR

This study evaluates two diphosphonates labeled with 161Tb as potential treatments for bone diseases, showing high bone targeting and safety in animal tests.

Contribution

The novel contribution is the successful radiolabeling of HEDP and ZOL with 161Tb and their evaluation as bone-targeting agents with high stability and selectivity.

Findings

161Tb-HEDP and 161Tb-ZOL showed high skeletal uptake and rapid blood clearance in rats.

161Tb-ZOL had lower renal and hepatic accumulation, indicating higher safety compared to 161Tb-HEDP.

DFT calculations confirmed that both ligands form stable complexes with Tb3+.

Abstract

Two diphosphonates, etidronic acid (HEDP) and zoledronic acid (ZOL), were radiolabelled with 161Tb and evaluated as potential bone-targeting radiopharmaceuticals. Radiolabeling was performed at pH 7, achieving high radiolabeling yields (greater than 98%) and demonstrating excellent in vitro stability in saline and human serum. Both radiolabeled complexes exhibited hydrophilic behavior, a strong binding affinity to hydroxyapatite, and moderate to high plasma protein binding. Biodistribution studies in healthy Wistar rats demonstrated that 161Tb-HEDP and 161Tb-ZOL achieve high and stable skeletal uptake with rapid blood clearance and minimal soft tissue accumulation. 161Tb-HEDP favored higher initial bone localization, while 161Tb-ZOL showed lower renal and hepatic accumulation, indicating higher safety and selectivity. Compared to unchelated 161TbCl3, both diphosphonate complexes exhibited significantly higher bone-to-kidney and bone-to-liver ratios, resulting in superior targeting. Complementary experiments with non-radioactive terbium were performed to investigate the redox behavior and confirm complex formation, providing valuable insight into the stability and binding modes of the ligands. Both terbium and the ligands displayed well-defined redox behavior within the potential range of −1 to 1.7 V, with complex formation evidenced by shifts in the oxidation peaks. Density functional theory (DFT) calculations further supported these findings, showing that both phosphonate groups of a ligand coordinate to Tb3+, while the hydroxyl groups in HEDP enable intermolecular hydrogen bonding, contributing to additional structural stabilization. Results encourage further investigations of 161Tb-labeled diphosphonates as promising candidates for radionuclide therapy of bone metastases and other skeletal diseases.

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