When ring makes the difference: coordination properties of Cu²⁺/Cu⁺ complexes with sulfur-pendant polyazamacrocycles for radiopharmaceutical applications

Abstract

Three polyazamacrocyclic ligands, i.e. 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S) and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetrazacyclotetradecane (TE4S), were considered as potential chelators for the medically relevant copper radioisotopes. The ligands have been synthesized through facile, single-step...

Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation

“…These results are comparable to those obtained with DO4S and point out that the addition of a single carbon atom in the ligand scaffold does not markedly affect the labelling performances. This result agrees with the reported thermodynamic and kinetic data [33]. Conversely, TE4S (i.e., the 14-member ring ligand) showed markedly inferior labelling performance than DO4S and TRI4S as it always yielded modest results The severely reduced efficiency of DO4S, DO3S and DO3SAm with respect to the carboxylate-containing chelators (DO2A2S and NODAGA-RDG) can be attributed not only to a lower thermodynamic stability of their Cu 2+ complexes, but also to the slower kinetics of the complexation reaction owing to the non-anionic nature of the sulfur pendant arms, as previously pointed out with stable Cu 2+ complexes [1].…”

“…These results are comparable to those obtained with DO4S and point out that the addition of a single carbon atom in the ligand scaffold does not markedly affect the labelling performances. This result agrees with the reported thermodynamic and kinetic data [33]. Conversely, TE4S (i.e., the 14-member ring ligand) showed markedly inferior labelling performance than DO4S and TRI4S as it always yielded modest results (Figure 4B and Table S3), with only ~40% incorporation achieved using the highest considered chelator concentration.…”

“…Conversely, TE4S (i.e., the 14-member ring ligand) showed markedly inferior labelling performance than DO4S and TRI4S as it always yielded modest results (Figure 4B and Table S3), with only ~40% incorporation achieved using the highest considered chelator concentration. The superior radiolabelling capacity of TRI4S over TE4S can be justified by the greater thermodynamic stability of its cupric complex [33]. [ 64 Cu]Cu 2+ complexation with TE4S can be enhanced by increasing the reaction temperature: the highest incorporation (e.g., from 24% at RT to 74% at 70 • C at 25 MBq/nmol) was however accompanied by the formation of labelling by-products.…”

“…In the second series, the effect of the ring size on the properties of the resulting copper complexes was considered, leading to 1,4,7,10-tetrakis [2-(methylsulfanyl)ethyl]-1,4,7,10tetrazacyclotridecane (TRI4S) and 1,4,8,11-tetrakis [2-(methylsulfanyl)ethyl]-1,4,8,11tetrazacyclotetradecane (TE4S) (Figure 1E) [33]. As a result, the thermodynamic, kinetic and structural properties of the Cu 2+/+ complexes formed with these sulfur-bearing ligands were investigated demonstrating that they can be promising scaffolds for cutting-edge copper-based radiopharmaceuticals [1,33]. The encouraging results prompted us to further evaluate our chelators in a radioactive environment to fully assess their candidacy for nuclear medicine applications.…”

“…Finally, in 1,7bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), the two opposite carboxylic arms of DOTA have been replaced with sulfur-containing ones, to produce a chelator with hybrid coordination capability between DOTA and DO4S (Figure 1D) [32]. In the second series, the effect of the ring size on the properties of the resulting copper complexes was considered, leading to 1,4,7,10-tetrakis [2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S) and 1,4,8,11-tetrakis [2-(methylsulfanyl)ethyl]-1,4,8,11tetrazacyclotetradecane (TE4S) (Figure 1E) [33]. As a result, the thermodynamic, kinetic and structural properties of the Cu 2+/+ complexes formed with these sulfur-bearing ligands were investigated demonstrating that they can be promising scaffolds for cutting-edge copper-based radiopharmaceuticals [1,33].…”