Comparative Evaluation of Chelator‐Conjugated Peptides for Lead‐Labeled SSTR2‐Targeted Theranostics: Integrated Computational Modeling and Preclinical Validation

Lead‐212 ( 212 Pb)‐based targeted alpha therapy is a promising approach for somatostatin receptor subtype 2 (SSTR2)‐positive neuroendocrine tumors (NETs), yet chelator selection can markedly influence radiochemical and biological behavior. An integrated computational and experimental approach is used to compare DOTA‐, PSC‐, and DOTAM‐conjugated Tyr 3 ‐octreotate (TATE). Density functional theory (DFT) reveals distinct differences in lead(II) (Pb 2+ ) and bismuth(III) (Bi 3+ ) complexes, including interaction energies, coordination geometry, electrostatic properties, conformational flexibility, and kinetic accessibility. Experimental evaluation with 203 Pb demonstrates >98% radiolabeling efficiency and >97% apparent radiochemical stability for all three conjugates, while cellular uptake, biodistribution, single‐photon emission computed tomography/computed tomography (SPECT/CT) imaging, and dosimetry reveal marked chelator‐dependent differences. DOTAM‐TATE exhibits high and sustained tumor uptake but greater normal‐organ retention, whereas PSC‐TATE combines substantial tumor uptake with lower renal and systemic retention, resulting in the most favorable tumor‐to‐kidney profile. Together, these findings show that Pb‐chelator performance reflects a balance among thermodynamic stabilization, coordination kinetics, conformational adaptability, and physicochemical properties, providing mechanistic guidance for the rational design of Pb‐based targeted radiopharmaceuticals.