Towards ²¹³Bi alpha-therapeutics and beyond: Unravelling the foundations of efficient Bi^IIIcomplexation by DOTP

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 BiIII-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 BiIII-complexes. In this work, a thorough study of the thermodynamics and kinetics of formation of BiIII-DOTP including radio-labelling and the comparison with the congener BiIII-DOTA is undertaken. The BiIII-DOTP complex is characterised by a fast formation kinetics (kBi(H2DOTP) = 0.33 s-1), an outstanding thermodynamic stability (log KBiDOTP = 38.67) and an impressive kinetic inertness (t1/2pH=3 = 47 600 h). The results clearly demonstrate that DOTP is a better chelating agent for BiIII both in terms of thermodynamic stability and in terms of kinetics of formation, with clear advantages in the radiolabelling of short-lived bismuth isotopes.