Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy.
Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 8, 35131 Padova, Italy.
Molecules. 2022 Jun 28;27(13):4158. doi: 10.3390/molecules27134158.
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-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 and Cu. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [Cu]Cu and the stability of the [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 [Cu]Cu complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [Cu][Cu(DO2A2S)] revealed a behavior similar to other [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.
当铜放射性同位素通过与肿瘤靶向载体偶联的螯合剂牢固配位时，通常用于癌症成像和治疗。然而，生物触发的 Cu-Cu 氧化还原开关可能会限制所得配合物在体内的完整性，导致去金属化过程。这种意外的途径预计会受到含有 N、O 和 S 供体的螯合剂的阻碍，这些供体适当地补充了 Cu 和 Cu 的边界硬和软性质。在这项工作中，评估了一系列富 S 的多氮大环螯合剂与 [Cu]Cu 的标记性能及其 [Cu]Cu 配合物的稳定性。在所考虑的螯合剂中，1,7-双[2-(甲硫基)乙基]-4,10,二乙酸-1,4,7,10-四氮杂环十二烷（DO2A2S）获得了最佳结果。在温和的反应条件下，以高摩尔活性标记 DO2A2S，其 [Cu]Cu 配合物在人血清中 24 小时内保持优异的完整性。用 [Cu][Cu(DO2A2S)] 在 BALB/c 裸鼠中进行的生物分布研究显示出与其他 [Cu]Cu 标记的环辛烷衍生物相似的行为，这些衍生物具有高肝和肾摄取，这可能归因于转金属化现象或完整配合物的代谢处理。
