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

• Published in: Inorganic chemistry frontiers 2024-10, Vol.11 (21), p.7307-7323
• Main Authors: Grieve, Melyssa L, Patrick R W J Davey, Bernhardt, Paul V, syth, Craig M, Paterson, Brett M
• Format: Article
• Language: English
• Subjects: Bismuth; Chelating agents; Complexation; Diethylenetriamine pentaacetic acid; Radiochemistry; Radiolabelling; Reaction time; Room temperature
• ISSN: 2052-1545; 2052-1553
• DOI: 10.1039/d4qi01338g

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.