| Summary: | 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<sup>2+</sup>-Cu<sup>+</sup> 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<sup>2+</sup> and Cu<sup>+</sup>. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [<sup>64</sup>Cu]Cu<sup>2+</sup> and the stability of the [<sup>64</sup>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 [<sup>64</sup>Cu]Cu<sup>2+</sup> complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [<sup>64</sup>Cu][Cu(DO2A2S)] revealed a behavior similar to other [<sup>64</sup>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.
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