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

Targeted alpha therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide Bi-213(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 Bi-205/206 mixture was used as a model of Bi-213 in labelling, stability, and biodistribution experiments, allowing the efficiency of [Bi-213(AAZTA-C4-TATE)](-) to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [Bi-213(DOTA-TATE)](-).