Tuning the Framework of Thioether-Functionalized Polyazamacrocycles: Searching for a Chelator for Theranostic Silver Radioisotopes

Silver-111 is an attractive unconventional candidate for targeted cancer therapy as well as for single photon emission computed tomography and can be complemented by silver-103 for positron emission tomography noninvasive diagnostic procedures. However, the shortage of chelating agents capable of forming stable complexes tethered to tumor-seeking vectors has hindered their in vivo application so far. In this study, a comparative investigation of a series of sulfur-containing structural homologues, namely, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetraazacyclotetradecane (TE4S) was conducted to appraise the influence of different polyazamacrocyclic backbones on Ag⁺ complexation. The performances of these macrocycles were also compared with those of the previously reported Ag⁺/[¹¹¹Ag]Ag⁺-chelator 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S). Nuclear magnetic resonance data supported by density functional theory calculations and X-ray crystallographic results gave insights into the coordination environment of these complexes, suggesting that all of the donor atoms are generally involved in the metal coordination. However, the modifications of the macrocycle topology alter the dynamic binding of the pendant arms or the conformation of the ring around the metal center. Combined pH/pAg-potentiometric and spectroscopic experiments revealed that the 12-member N₄ backbone of DO4S forms the most stable Ag⁺ complex while both the enlargement and the shrinkage of the macrocyclic frame dwindle the stability of the complexes. Radiolabeling experiments, conducted with reactor-produced [¹¹¹Ag]Ag⁺, evidenced that the thermodynamic stability trend is reflected in the ligand’s ability to incorporate the radioactive ion at high molar activity, even in the presence of a competing cation (Pd²⁺), as well as in the integrity of the corresponding complexes in human serum. As a consequence, DO4S proved to be the most favorable candidate for future in vivo applications.