Rapid and stable complexation of the α-generators bismuth-212 and lead-212 with a tetraazamacrocyclic chelator bearing thiosemicarbazone pendant arms

Abstract

The bis(thiosemicarbazone) chelator featuring the 1,4,7,10-tetrazacyclododecane macrocyclic scaffold, 1,4,7,10-tetraazacyclododecane 4,10-dimethyl 1,7-bis(4-methylthiosemicarbazone) (H₂DOTS), formed 8-coordinate N₆S₂ complexes with Bi³⁺ and Pb²⁺. Radiolabelling with [²¹²Pb]Pb²⁺ at room temperature achieved 92.2 ± 0.8% radiochemical conversion with a chelator concentration of 10⁻⁵ M at pH 5.5 (30 min reaction time), and 97.4 ± 1.6% at pH 7.4 (30 min reaction time) and a radioactivity to chelator ratio of ∼10 MBq nmol⁻¹. [²¹²Pb][Pb(H₂DOTS)]²⁺ was stable (90.0 ± 2.2% intact) in human serum over 48 h. Radiolabelling with [²¹²Bi]Bi³⁺ at room temperature achieved 95.0 ± 3.8% radiochemical conversion with a chelator concentration of 10⁻⁵ M at pH 5.5 (10 min reaction time). [Bi(DOTS)]⁺ was stable (95% intact) in the presence of a 1000-fold excess of diethylenetriaminepentaacetic acid for 2 days. The efficient complexation and remarkable kinetic inertness of H₂DOTS with both [²¹²Bi]Bi³⁺ and [²¹²Pb]Pb²⁺ matches or surpasses the properties of the chelators 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid (H₄DOTP) and 2-(4-isothiocyanatobenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic amide (p-SCN-Bn-TCMC), respectively, demonstrating the unique potential of H₂DOTS for developing theranostic radiopharmaceuticals.