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 trig-gered Cu²⁺-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 Cu²⁺ and Cu⁺ . In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [⁶⁴Cu]Cu²⁺ and the stability of the [⁶⁴Cu]Cu-complexes thereof were evaluated. Among the chela-tors 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 [⁶⁴Cu]Cu²⁺ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [⁶⁴Cu][Cu(DO2A2S)] revealed a behavior similar to other [⁶⁴Cu]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.