<p class="MsoNormal" style="margin-bottom: 12.0pt; text-align: left; mso-line-height-alt: 14.0pt; layout-grid-mode: char; mso-layout-grid-align: none;" align="left">¹⁶¹Tb-BPAMD as a High-Affinity Agent for Skeletal Targeting: Radiochemical and Biodistribution Insights

Background: Bone-seeking radiopharmaceuticals based on bisphosphonates enable targeted therapy of skeletal metastases. They are ideal 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 aimed to investigate the potential of the specific DOTA conjugated bisphosphonate - BPAMD (4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10 tetraazacyclododec-1-yl)acetic acid) radiolabeled with 161Tb as a next-generation of bone-targeted radiopharmaceutical. Methods: BPAMDwas radiolabeled with 161Tb and 177Lu under mild conditions (pH 4.5, 95°C, 30min); subsequently the radiochemical purity was assessed by radio-TLC and radioelectrophoresis. Physicochemical properties (charge, lipophilicity, protein binding), in vitro stability (saline and human serum, 48h), and hydroxyapatite binding were evaluated for 161Tb-BPAMD. Biodistribution was studied in healthy Wistar rats (n=3 per time point) at 2h, 24h, and 7 days post-injection. Complementary DFT calculations explored the coordination chemistry of Tb3+ and Lu3+ with BPAMD. Results: Both complexes achieved &gt;98% radiochemical yield. 161Tb-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 (&gt;97% at 48h), and strong hydroxyapatite affinity (&gt;98% with ≥10 mg HAP). Biodistribution showed high, stable bone uptake (8.06% ID/g at 2h; 6.70% ID/g at 24h; 5.31% ID/g at 7d) with rapid blood clearance (&lt;0.001% ID/g at 24h), and low non-target retention. To contextualize its performance, 161Tb-BPAMD was compared with 177Lu-BPAMD, which demonstrated similarly strong skeletal retention (8.74% ID/g at 2h; 8.08% ID/g at 24h; 5.25% ID/g at 7d) but comparatively higher non-target organ uptake. Complementary DFT calculations indicate that both Tb3+ and Lu3+ favor octa-coordinated BPAMD complexes. Conclusions: 161Tb-BPAMD exhibits excellent radiochemical and pharmacokinetic properties, with enhanced biodistribution selectivity over 177Lu-BPAMD. Combined with the radiobiological advantages of 161Tb, it represents a promising theranostic candidate for targeted therapy of bone metastases.