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

Abstract

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.