Impact of Ring Topology in Thioether-Containing Polyazamacrocycles on the Chelation of the Auger Electron Emitter Mercury-197m/g

Abstract The development of chelators forming stable and inert complexes with Hg2+ is essential for harnessing the Auger electron-emitting radionuclide [197m/gHg]Hg2+ for cancer theranostics. Herein, thioether-containing polyazamacrocycles with distinct ring topologies (NO3S, TACD3S, DO4S, and TE4S) were evaluated to determine how backbone architecture and donor set govern Hg2+ binding. All ligands bound natHg2+ rapidly at ambient temperature, suggesting that ring topology has no influence on the complexation kinetics. In contrast, the thermodynamic behavior depends on the ligand structure: replacement of ethylenic with propylenic linkers decreases the complex stability, whereas reducing the number of donor atoms from eight to six has a moderate effect within fully ethylenic frameworks. NMR spectroscopy, DFT calculations, and crystallographic data reveal topology-dependent Hg2+ coordination trends. NO3S and TACD3S form six-coordinate N3S3 environments. In contrast, DFT-optimized structures for DO4S and TE4S correspond to a N4S2 coordination mode, while solution NMR shows a single averaged SCH3 resonance, indicating equivalent thioether environments on the NMR time scale. Radiolabeling with [197m/gHg]Hg2+ demonstrated a topology-dependent trend: NO3S enabled quantitative incorporation at 50 °C and outperformed DO4S, whereas TACD3S and TE4S failed to achieve full complexation. In human serum, [197m/gHg][Hg(NO3S)]2+ is exceptionally inert over 24 h, identifying NO3S as a promising scaffold for bifunctionalization and future in vivo application of this theranostic pair.