Figure S6 1H NMR of compound Re(CO)3L2 from Synthesis of novel technetium-99 m 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]ethylenediamine-N,N'-diacetic acid, L1) is a common bifunctional chelating agent in preparation of 68Ga-radiopharmaceuticals. Due to its high stability constant for the Ga3+ complex (logKGaL = 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. [99 mTc][Tc(CO)3(H2O)3]+ is an excellent precursor for radiolabelling of biomolecules. The aim of this study was to develop a novel preparation method of 99 mTc-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, L2), a derivative of HBED-CC, was designed and synthesized. Both L1 and L2 were radiolabelled by [99 mTc][Tc(CO)3(H2O)3]+ successfully for the first time. In order to explore the coordination mode of metal and chelates, non-radioactive Re(CO)3L1 and Re(CO)3L2 were synthesized and characterized spectroscopically. Tc(CO)3L1 and Tc(CO)3L2 in solution were calculated by density functional theory and were analysed with radio-HPLC chromatograms. It showed that [99 mTc]Tc(CO)3L2 forms two stable diastereomers in solution, which is similar to those of [68Ga]Ga-HBED-CC complexes. Natural bond orbital analysis through the natural population charges revealed a charge transfer between [99 mTc][Tc(CO)3]+ and L1 or L2. 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 99 mTc-radiopharmaceuticals as diagnostic imaging agents.