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

Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu(2+)-Cu(+) redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu(2+) and Cu(+). In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [(64)Cu]Cu(2+) and the stability of the [(64)Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [(64)Cu]Cu(2+) complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [(64)Cu][Cu(DO2A2S)] revealed a behavior similar to other [(64)Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex.