Evaluation of ¹⁶¹Tb-Labeled DOTA-Ibandronate for Targeted Radionuclide Therapy in Bone Metastases.

Abstract

Building upon our previous work on [68Ga]Ga/[177Lu]Lu-DOTA-Ibandronate and its demonstrated clinical applicability, this study investigates the biological behavior and translational potential of the novel therapeutic radiopharmaceutical terbium-161 (161Tb)-labeled DOTA-IBA. The radiolabeling parameters of [161Tb]Tb-DOTA-IBA were first optimized, followed by a systematic assessment of its physicochemical characteristics. Biodistribution, micro-SPECT/CT imaging, and therapeutic efficacy were evaluated in a 4T1 mouse model of bone metastasis to determine pharmacokinetics and bone-targeting capacity. Safety was verified through dose-escalation experiments. Furthermore, a preliminary clinical evaluation was performed in one volunteer with bone metastases to validate safety and initial therapeutic efficacy. [161Tb]Tb-DOTA-IBA was obtained with radiochemical purity exceeding 98%, demonstrating excellent bone-targeting selectivity and retention, with a 24 h bone uptake of 30.61 ± 4.61% ID/g, which is substantially higher than in soft tissues. In a patient receiving 370 MBq, marked pain relief was achieved, reflected by decreased VAS scores, with therapeutic benefit lasting 8-12 weeks and no observed toxic reactions. The compound exhibited favorable pharmacokinetics and safety, with no ≥ grade 3 adverse events. Overall, [161Tb]Tb-DOTA-IBA displayed high tumor-to-background ratios and excellent pharmacokinetic behavior. Early human data confirmed its safety and therapeutic potential. The complementary use of [68Ga]Ga/[161Tb]Tb-DOTA-IBA enables a unified diagnostic-therapeutic platform for the management of bone metastases, providing an innovative, targeted treatment option capable of improving both quality of life and survival in patients with advanced skeletal disease.