Towards 213Bi alpha-therapeutics and beyond: unravelling the foundations of efficient BiIII complexation by DOTP

Abstract

Bismuth isotopes are attracting increasing attention for their potential applications in diagnostics and therapy. The emerging use of ²¹³Bi in targeted α-therapy (TAT) is a particularly relevant example because it is available from radionuclide generators. A fast formation of stable Bi^III-complexes is important for the safe and efficient preparation of labelled (bio)conjugates. Macrocyclic chelating agents are currently the best choice in terms of stability of the corresponding Bi^III-complexes. In this work, a thorough study of the thermodynamics and kinetics of formation of Bi^III-DOTP including radio-labelling and the comparison with the congener Bi^III-DOTA is undertaken. The Bi^III-DOTP complex is characterised by a fast formation kinetics (k_Bi(H2DOTP) = 0.33 s⁻¹), an outstanding thermodynamic stability (log K_BiDOTP = 38.67) and an impressive kinetic inertness (t_1/2^pH=3 = 47 600 h). The results clearly demonstrate that DOTP is a better chelating agent for Bi^III both in terms of thermodynamic stability and in terms of kinetics of formation, with clear advantages in the radiolabelling of short-lived bismuth isotopes.