Boosting Bismuth(III) Complexation for Targeted α‐Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA

Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide (213)Bi(III) shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates Bi(III) at room temperature, leading to a robust complex. A comprehensive study of the structural, thermodynamic and kinetic properties of [Bi(AAZTA)](−) is reported, along with bifunctional [Bi(AAZTA‐C4‐COO(−))](2−) and the targeted agent [Bi(AAZTA‐C4‐TATE)](−), which incorporates the SSR agonist Tyr(3)‐octreotate. An unexpected increase in the stability and kinetic inertness of the metal chelate was observed for the bifunctional derivative and was maintained for the peptide conjugate. A cyclotron‐produced (205/206)Bi mixture was used as a model of (213)Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [(213)Bi(AAZTA‐C4‐TATE)](−) to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [(213)Bi(DOTA‐TATE)](−).