Selective Chelation of the Exotic Meitner-Auger Emitter Mercury-197 m/g with Sulfur-Rich Macrocyclic Ligands: Towards the Future of Theranostic Radiopharmaceuticals

Abstract

Mercury-197 m/g are a promising pair of radioactive isomers for incorporation into a theranostic as they can be used as a diagnostic agent using SPECT imaging and a therapeutic via Meitner-Auger electron emissions. However, the current absence of ligands able to stably coordinate 197m/gHg to a tumour-targeting vector precludes their use in vivo. To address this, we report herein a series of sulfur-rich chelators capable of incorporating 197m/gHg into a radiopharmaceutical. 1,4,7,10-Tetrathia-13-azacyclopentadecane (NS4) and its derivatives, (2-(1,4,7,10-tetrathia-13-azacyclopentadecan-13-yl)acetic acid (NS4-CA) and N-benzyl-2-(1,4,7,10-tetrathia-13-azacyclopentadecan-13-yl)acetamide (NS4-BA), were designed, synthesized and analyzed for their ability to coordinate Hg2+ through a combination of theoretical (DFT) and experimental coordination chemistry studies (NMR and mass spectrometry) as well as 197m/gHg radiolabeling studies and in vitro stability assays. The development of stable ligands for 197m/gHg reported herein is extremely impactful as it would enable their use for in vivo imaging and therapy, leading to personalized treatments for cancer.