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.

Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals

“…197m/g Hg 2+ radiolabeling of DOTA was also conducted for comparison with both TCMC and the bifunctional derivatives. No radiometal incorporation (radiochemical yield, RCY = 0%) was observed under any tested condition with DOTA ( C DOTA = 10 −4 M, 1 h, ambient temperature or 80 °C, pH 5), as previously observed ( Randhawa et al, 2023 ). 197m/g Hg 2+ radiolabeling of TCMC resulted in a very moderate increase in radiometal incorporation (RCY = 5.2 ± 1.7%; C TCMC = 10 −4 M, 1 h, 80 °C, pH 5) ( Figure 5 ; Supplementary Figure S45 ).…”

“…As isothiocyanate-containing compounds are known to readily undergo hydrolysis ( Kawakishi and Namiki, 1969 ), solutions were freshly prepared the day of use. Radiolabeling procedures closely followed those previously developed by our group ( Randhawa et al, 2023 ). Stock solutions of TCMC, DOTA, p -SCN-Bn-TCMC, p -SCN-Bn-DOTA, and TCMC-PMSA (10 –3 M) in deionized water (dilute HCl for TCMC) were used to prepare serial dilutions at ligand concentrations of 10 −4 , 10 −5 M, 10 −6 M, and 10 −7 M which were diluted in deionized water.…”

“…GSH competition assay procedures closely followed those previously developed by our group ( Randhawa et al, 2023 ). [ 197m/g Hg][Hg( p -SCN-Bn-TCMC)] 2+ and [ 197m/g Hg][Hg (TCMC-PSMA)] 2+ (prepared as described above) or radiolabeling controls (deionized water instead of the ligand) were added to a 50 mM L -glutathione (GSH) solution (1:22 v / v GSH:reaction solution dilution), and the mixtures were incubated at 37 °C over 24 h. The final GSH concentration was chosen to mimic in vivo conditions within cells (2.12 mM) ( Dickinson and Forman, 2002 ).…”

“…Given the limited literature on 197m/g Hg labeling with chelators, elucidation of the structure, bonding and radiolabeling behaviours of nat Hg/ 197m/g Hg 2+ with commercially available chelators is fundamental knowledge needed to gain a better understanding of the coordination behavior of radiomercury. Although the identification of better-suited 197m/g Hg 2+ chelators such as N-benzyl-2-(1,4,7,10-tetrathia-13-azacyclopentadecan-13-yl)acetamide (NS 4 -BA) have been most recently reported by our group ( Randhawa et al, 2023 ), the studies presented herein will provide necessary information to guide the future design of chelators for this isomer pair, crucial for its future use in clinical and preclinical applications.…”

Adjuvant Auger Electron-Emitting Radioimmunotherapy with [111In]In-DOTA-Panitumumab in a Mouse Model of Local Recurrence and Metastatic Progression of Human Triple-Negative Breast Cancer

“…Emitting 19.4 to as many as 36.5 AE per decay, 197m Hg and 197 Hg, 201 Tl, 119 Sb, 193m Pt, and 195m Pt are promising alternative radionuclides for the design of more potent AE RIT agents . Indeed, cellular dosimetry calculations estimated an average of 2–3 fold higher energy deposition per decay for 197m Hg compared to 111 In (7.4 AE/decay), and novel bifunctional chelators for radiolabeling antibodies with 197m Hg have recently been reported …”