School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia.
Inorg Chem. 2011 Jul 18;50(14):6701-10. doi: 10.1021/ic200681s. Epub 2011 Jun 13.
The synthesis of new cage amine macrobicyclic ligands with pendent carboxylate functional groups designed for application in copper radiopharmaceuticals is described. Reaction of Cu((NH(2))(2)sar) (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) with either succinic or glutaric anhydride results in selective acylation of the primary amine atoms of Cu((NH(2))(2)sar) to give derivatives with either one or two aliphatic carboxylate functional groups separated from the cage amine framework by either a four- or five-atom linker. The Cu(II) serves to protect the secondary amine nitrogen atoms from acylation, and can be removed to give the free ligands. The newly appended carboxylate functional groups can be used as sites of attachment for cancer-targeting peptides such as Lys(3)-bombesin. The synthesis of the first dimeric sarcophagine-peptide conjugate, possessing two Lys(3)-bombesin peptides tethered to a single cage amine, is presented. This species has been radiolabeled with copper-64 at ambient temperature and there is minimal dissociation of Cu(II) from the conjugate even after two days of incubation in human serum.
描述了具有侧链羧酸盐官能团的新型笼状胺大环配体的合成，这些配体旨在应用于铜放射性药物。Cu((NH(2))(2)sar)（sar = 3,6,10,13,16,19-六氮杂双环[6.6.6]icosane）与琥珀酸酐或戊二酸酐反应，选择性酰化Cu((NH(2))(2)sar)的伯胺原子，得到具有一个或两个脂肪族羧酸盐官能团的衍生物，这些官能团通过四或五原子连接体与笼状胺骨架隔开。Cu(II) 用于保护仲胺氮原子免受酰化，并且可以去除以得到游离配体。新附加的羧酸盐官能团可以用作连接癌症靶向肽的附着点，例如 Lys(3)-蛙皮素。介绍了第一个二聚 sarcophagine-肽缀合物的合成，该缀合物具有两个连接到单个笼状胺上的 Lys(3)-蛙皮素肽。该物质已在环境温度下用铜-64 进行放射性标记，即使在人血清中孵育两天后，铜(II)也很少从缀合物中解离。
