Background: Bone-seeking radiopharmaceuticals based on bisphosphonates enable targeted therapy of skeletal metastases. They are suitable carriers for therapeutic radionuclides such as terbium-161 (161Tb), a β− emitter that additionally releases short-range conversion and Auger electrons, which may enhance radiation dose delivery to small lesions. This study explored the potential of the well-established DOTA conjugated bisphosphonate BPAMD (4- (bis (phosphonomethyl) ) carbamoylmethyl-7, 10-bis (carboxymethyl) -1, 4, 7, 10 tetraazacyclododec-1-yl) acetic acid) radiolabeled with 161Tb as a bone-targeted radiopharmaceutical, focusing on the theranostic and radiophysical advantages conferred by the radionuclide. Methods: BPAMD was radiolabeled with 161Tb and 177Lu under mild conditions (pH 4. 5, 95 °C, 30 min) ; subsequently, the radiochemical purity was assessed by radio-TLC. Physicochemical properties (charge, lipophilicity, protein binding), in vitro stability (saline and human serum, 48 h), and hydroxyapatite (HAP) binding were evaluated for 161TbTb-BPAMD. Biodistribution was investigated in healthy Wistar rats (n = 3 per time point) at 2 h, 24 h, and 7 days post-injection. Computational density functional theory (DFT) analyses were performed to explore the coordination chemistry of Tb3+ and Lu3+ with BPAMD. Results: Both complexes achieved a radiochemical yield of greater than 98%. 161TbTb-BPAMD exhibited negative charge, high hydrophilicity (logP = −3. 92 ± 0. 13), low protein binding (19. 07 ± 1. 01%), excellent radiochemical stability under simulated physiological conditions (>97% at 48 h), and strong hydroxyapatite affinity (>98% with ≥10 mg HAP). Biodistribution showed high, stable bone uptake (8. 06% ID/g at 2 h; 6. 70% ID/g at 24 h; 5. 31% ID/g at 7 d) with rapid blood clearance (<0. 001% ID/g at 24 h) and low non-target retention. To contextualize its performance, 161TbTb-BPAMD was compared with 177LuLu-BPAMD, which demonstrated similarly strong skeletal retention (8. 74% ID/g at 2 h; 8. 08% ID/g at 24 h; 5. 25% ID/g at 7 d) but comparatively higher non-target organ uptake. DFT calculations indicate that both Tb3+ and Lu3+ favor octa-coordinated BPAMD complexes. Conclusions: 161TbTb-BPAMD exhibits excellent radiochemical and pharmacokinetic properties, with enhanced biodistribution selectivity over 177LuLu-BPAMD. Combined with the radiobiological advantages of 161Tb, it represents a promising theranostic candidate for targeted therapy of bone metastases.
Radović et al. (Sat,) studied this question.