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, 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. [99mTc][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 99mTc-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 [99mTc][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 [99mTc]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 [99mTc][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 99mTc-radiopharmaceuticals as diagnostic imaging agents.

In addition, in the HRMS spectrum (Fig2 in ESM) of [Re(CO)3L2] , there is no data corresponding to the measured values described in the experimental section (HRMS calcd. For ReC39H43N10O15 (M+H)+: 1079.7, found 1079.7827). Please check other experimental data descibed in the ESM. For the DFT calculation results, the coordinates of the calculation results for each structure should be described in ESM. If authors had performed the calculations in the solution, the authors should refer to the details of how to handle calculations in solution (for example, the polarizable continuum model (PCM) to include solvent effects).
Anyway, the authors should pay attention to the the manuscript to make revised version.

14-Aug-2019
Dear Dr Fang: Title: Synthesis of novel technetium-99m tricarbonyl-HBED-CC complexes and structural prediction in solution by density functional theory Manuscript ID: RSOS-191247 Thank you for your submission to Royal Society Open Science. The chemistry content of Royal Society Open Science is published in collaboration with the Royal Society of Chemistry.
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Once again, thank you for submitting your manuscript to Royal Society Open Science and I look forward to receiving your revision. If you have any questions at all, please do not hesitate to get in touch. ********************************************** RSC Associate Editor: Comments to the Author: (There are no comments.) RSC Subject Editor: Comments to the Author: (There are no comments.) ********************************************** Reviewers' Comments to Author: Reviewer: 1 Comments to the Author(s) This manuscript outlined the synthesis of technetium tricarbonyl complexes with N,O-based ligands, combined with density functional calculations to analyze the interaction energies and frontier molecular orbitals. This is a very nice example of combined experimental and computational work. It may be published after addressing the following minor issues: 1. The standard B3LYP functional was used for the calculations. The only concern is that dispersion was not included, and single point calculations with Grimme's dispersion correction should be added. 2. It seems that electronic energies or enthalpies were reported, but Gibbs energies may be reported for comparison. 3. Solvation effect in water (if in aqueous solution) should be considered using the SMD solvation model. 4. Coordinates should be given in the supporting information.
Comments to the Author(s) The authors explained the synthesis and structural study of two complexes including technetium-99m with multidentate ligands. It seems that there are many errors and incorrect descriptions in the manuscript. The authors should pay more attention to make manuscript. I feel this manuscript is not suitable for Royal Society Open Science at present version. I recommend acceptance of the paper if the authors manage to address some major issues.  -191247.R1 (Revision) Review form: Reviewer 2

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