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Cadmium, an extremely toxic heavy metal, poses significant health risks to humans. Despite persistent research efforts, the development of effective treatments for cadmium intoxication remains a challenge. This study aims to establish the chemical groundwork for improved chelation therapy options against cadmium poisoning. Herein, the coordination chemistry of a series of sulfur-rich macrocycles featuring different polyamine backbones (NO3S, TACD3S, DO4S, TRI4S, and TE4S) was investigated. Our results demonstrate that DO4S exhibits exceptional Cd 2+ scavenging ability, forming the most thermodynamically stable complex among the studied chelators. The stability of the Cd 2+ complexes decreases in the following order: DO4S (pCd = 19.8) ≫ NO3S (pCd = 11.0) ∼ TRI4S (pCd = 10.9) ≫ TE4S (pCd = 7.8) > TACD3S (pCd = 7.3). DFT calculations demonstrated that the backbone polarization properties dictate the observed reduced stability when shifting from DO4S to the other ligands. DO4S showed superior affinity when compared to the state-of-the-art Cd 2+ chelators such as EDTA (pCd = 16.7), DTPA (pCd = 17.4), and DMSA (pCd = 13.2). The findings from this study underscore the potential of the examined chelating agents, with particular reference to DO4S, paving the way for the development of advanced chelation therapies to combat cadmium poisoning.

The biologically triggered reduction of Cu 2+ to Cu + has been postulated as a possible in vivo decomplexation pathway in 64/67 Cu-based radiopharmaceuticals. In an attempt to hinder this phenomenon, we have previously developed a family of S-containing polyazamacrocycles based on 12-, 13-, or 14-membered tetraaza rings able to stabilize both oxidation states. However, despite the high thermodynamic stability of the resulting Cu 2+/+ complexes, a marked [ 64 Cu]Cu 2+ release was detected in human serum, likely as a result of the partially saturated coordination sphere around the copper center. In the present work, a new hexadentate macrocyclic ligand, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), was synthesized by hypothesizing that a smaller macrocyclic backbone could thwart the observed demetalation by fully encapsulating the copper ion. To unveil the role of the S donors in the metal binding, the corresponding alkyl analogue 1,4,7-tris- n -butyl-1,4,7-triazacyclononane (TACN- n -Bu) was considered as comparison. The acid-base properties of the free ligands and the kinetic, thermodynamic, and structural properties of their Cu 2+ and Cu + complexes were investigated in solution and solid (crystal) states through a combination of spectroscopic and electrochemical techniques. The formation of two stable mononuclear species was detected in aqueous solution for both ligands. The pCu 2+ value for NO3S at physiological pH was 6 orders of magnitude higher than that computed for TACN- n -Bu, pointing out the significant stabilizing contribution arising from the Cu 2+ -S interactions. In both the solid state and solution, Cu 2+ was fully embedded in the ligand cleft in a hexacoordinated N 3 S 3 environment. Furthermore, NO3S exhibited a remarkable ability to form a stable complex with Cu + through the involvement of all of the donors in the coordination sphere. Radiolabeling studies evidenced an excellent affinity of NO3S toward [ 64 Cu]Cu 2+ , as quantitative incorporation was achieved at high apparent molar activity (∼10 MBq/nmol) and under mild conditions (ambient temperature, neutral pH, 10 min reaction time). Human serum stability assays revealed an increased stability of [ 64 Cu][Cu(NO3S)] 2+ when compared to the corresponding complexes formed by 12-, 13-, or 14-membered tetraaza rings.

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 + /[ 111 Ag]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 N 4 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 [ 111 Ag]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 (Pd 2+ ), 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.

The Cu 2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV-vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV-vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag + -Cu 2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu 2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu 2+ complexes in aqueous solution were investigated by UV-vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO 3 )]·NO 3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu 2+ to Cu + on the CV time scale. The Cu + complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu 2+ and Cu + complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu + , often observed for other well-known chelators that can stabilize only Cu 2+ .