HBED-NN: A Bifunctional Chelator for Constructing Radiopharmaceuticals

Abstract

Radiometal-based radiopharmaceuticals bearing bifunctional HBED chelators are powerful radiotracers for cancer diagnosis and therapy. Bifunctional HBED chelators make strong complexes with trivalent gallium and are able to bind to bioactive molecules through covalent bonds. However, thus far, no bifunctional HBED chelator capable of direct conjugation via click chemistry has been reported. We hereby introduce HBED-NN as a structurally new bifunctional HBED chelator for direct click coupling. We also investigated the complex chemistry of [Ga-(HBED-NN)] for potential use in gallium-based radiopharmaceuticals.

H4HBEDpa: Octadentate Chelate after A. E. Martell

“…It has been confirmed that iron depletion is an effective strategy as many studies suggest that iron overload in cells is related to the generation and development of cancer . Subsequently, chelators with hard phenolic O-donor atoms such as EHPG and HBED (Chart ) were developed for Fe 3+ chelation therapy. , Over the years, significant work across research laboratories and in clinical trials led to the development of bifunctional versions of HBED and its applications predominantly for [ 68 Ga]­Ga-based radiopharmaceuticals. − …”

Synthesis of a polyaminocarboxylate-based aluminum complex and its structural studies using 1H{13C}-HMBC NMR and a Karplus-type function

“…7 In contrast, the HBED-NN ligand facilitates convenient reaction monitoring by 1 H NMR since the sharp triazolyl singlet at 8.4 ppm (in DMSO) occurs in an uncrowded downfield region. 3 Generally, triazolyl residue protons are very sensitive to structural modification, even to quite distant changes elsewhere in the molecule to which their δ H 's respond accordingly. [3][4][5] Thus, by utilizing the proton triazolyl singlet for reaction monitoring, the conversion and chemoselectivity of chelation is able to be followed and duly optimized.…”

“…25 The wellknown Karplus-type relationships for vicinal couplings between nuclei are functions relating 3 J's with the dihedral angles (α) between the nuclei. 26,27 They since have been developed for various systems (e.g., 25,28 however, they all exhibit quite similar trajectories, viz., 3 J is a maximum when α = 0°or 180°due to maximum overlap of orbitals and a minimum when α = 90°due to the orbitals being perpendicular to one another. The dihedral angle is not the only factor determining the size of 3 J, other factors such as bond length, order and angle as well as the presence of electronegative/positive substituents etc.…”

“…19 However, in contrast to [Al-HBED] − , other HBED hexacoordinate scaffolds such as [Fe-HBED] − , [Ti-HBED] and [Ga-HBED] − have had their structures determined. 3,11,12 Herein, we employed NMR in conjunction with DFT calculations to determine the coordination of the Al-HBED cage using the newly synthesized [Al-HBED-NN] − Na + complex (Scheme 1).…”

“…8,14 However, the content of the predominant complex species in the HBED chelation depends on a number of factors such as the reaction conditions, particularly the temperature, as well as the nature of the metal in terms of its size, valence, hardness/softness, etc. 3,7 Although the synthesis and application of the Al-HBED hexacoordinate complex ([Al-HBED] − ) have already been described in basic and applied research, it has not yet been investigated from a structural point of view; and even characterization data to support its existence have not been reported. [15][16][17][18] Only in one case was the occurrence of [Al-HBED] − reported in the research literature where it was detected by mass spectroscopy as a byproduct, but the compound was not isolated and characterized as a single substance.…”