Synthesis of novel technetium-99m tricarbonyl-HBED-CC complexes and structural prediction in solution by density functional theory calculation

HBED-CC (N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylene diamine-N,N'-diacetic acid, L(1)) is a common bifunctional chelating agent in preparation of (68)Ga-radiopharmaceuticals. Due to its high stability constant for the Ga(3+) complex (logK(GaL) = 38.5) and its acyclic structure, it is well known for a rapid and efficient radiolabelling at ambient temperature with Gallium-68 and its high in vivo stability. [(99m)Tc][Tc(CO)(3)(H(2)O)(3)](+) is an excellent precursor for radiolabelling of biomolecules. The aim of this study was to develop a novel preparation method of (99m)Tc-HBED-CC complexes. In this study, HBED-CC-NI (2,2'-(ethane-1,2-diylbis((2-hydroxy-5-(3-((2-(2-nitro-1H-imidazol-1-yl)ethyl)amino)-3-oxopropyl)benzyl)-azanediyl))-diacetic acid, L(2)), a derivative of HBED-CC, was designed and synthesized. Both L(1) and L(2) were radiolabelled by [(99m)Tc][Tc(CO)(3)(H(2)O)(3)](+) successfully for the first time. In order to explore the coordination mode of metal and chelates, non-radioactive Re(CO)(3)L(1) and Re(CO)(3)L(2) were synthesized and characterized spectroscopically. Tc(CO)(3)L(1) and Tc(CO)(3)L(2) in solution were calculated by density functional theory and were analysed with radio-HPLC chromatograms. It showed that [(99m)Tc]Tc(CO)(3)L(2) forms two stable diastereomers in solution, which is similar to those of [(68)Ga]Ga-HBED-CC complexes. Natural bond orbital analysis through the natural population charges revealed a charge transfer between [(99m)Tc][Tc(CO)(3)](+) and L(1) or L(2). The experimental results showed that tricarbonyl technetium might form stable complex with HBED-CC derivatives, which is useful for the future application of using HBED-CC as a bifunctional chelating agent in developing new (99m)Tc-radiopharmaceuticals as diagnostic imaging agents.