Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
J Inorg Biochem. 2011 Jun;105(6):821-32. doi: 10.1016/j.jinorgbio.2011.02.011. Epub 2011 Mar 22.
New macrocyclic 1,4,8,11-tetraazacyclotetradecane (cyclam) derivatives with 1, 2 and 4 neurotensin(8-13) units 4, 5 and 7 have been synthesized. Compounds 4 and 5 were prepared by the reaction of non-stabilized neurotensin(8-13) and cyclamtetrapropionic acid 2 using 1-ethyl-3-(3-dimethylaminocarbonyl)carbodiimide-hydrochloride and N-hydroxysulfosuccinimide. The tetrameric compound 7 was synthesized by Michael addition of neurotensin(8-13) acrylamide 6 and cyclam 1. The copper(II) complexation behavior of 4, 5 and 7 was investigated by UV/visible spectrophotometry and shows that the metal center resides inside the N4 chromophore with additional apical interactions established with pendant arms. The novel tetrabranched NT(8-13) cyclam 7 with nanomolar neurotensin receptor 1 binding affinity was efficiently radiolabeled with (64)Cu under mild conditions. (64)Cu⊂7 showed slow transchelation in the presence of a large amount of cyclam as competing ligand, while it completely remains intact in the presence of EDTA. The in vivo behavior of (64)Cu⊂7 was studied in rats and mice. The metabolic stability in rodent models was high with a half-life of intact (64)Cu⊂7 in plasma of 34 min in rats and 60 min in the mice, respectively. The binding affinity was high enough to demonstrate in vivo binding of (64)Cu⊂7 to NTR1 overexpressing HT-29 tumor xenotransplants in nude mice. Regarding elimination, (64)Cu⊂7 showed a substantial renal and reticuloendothelial accumulation. On the other hand, metabolization of the compound in vivo with a resulting metabolite-postulated to be the (64)Cu-cyclam-tetraarginine complex-also showed long retention in the circulating blood, preventing a better contrast of tumor imaging.
已合成了具有 1、2 和 4 个神经降压素（8-13）单元的新型大环 1,4,8,11-四氮杂环十四烷（环十四烷）衍生物 4、5 和 7。化合物 4 和 5 是通过不稳定的神经降压素（8-13）与环十四烷四丙酸 2 的反应，使用 1-乙基-3-（3-二甲基氨基羰基）碳二亚胺盐酸盐和 N-羟基琥珀酰亚胺制备的。四聚体化合物 7 是通过神经降压素（8-13）丙烯酰胺 6 和环十四烷 1 的迈克尔加成合成的。通过紫外/可见分光光度法研究了 4、5 和 7 的铜（II）络合行为，结果表明金属中心位于 N4 发色团内部，并且与悬垂臂建立了额外的顶端相互作用。具有纳摩尔神经降压素受体 1 结合亲和力的新型四臂 NT（8-13）环十四烷 7 在温和条件下有效用（64）Cu 进行放射性标记。（64）Cu⊂7 在大量环十四烷作为竞争配体存在下缓慢转金属化，而在 EDTA 存在下完全保持完整。在大鼠和小鼠中研究了（64）Cu⊂7 的体内行为。在啮齿动物模型中，代谢稳定性很高，完整的（64）Cu⊂7 在大鼠血浆中的半衰期为 34 分钟，在小鼠中为 60 分钟。结合亲和力足够高，可以证明（64）Cu⊂7 在裸鼠中过表达 HT-29 肿瘤异种移植物上与 NTR1 的体内结合。关于排泄，（64）Cu⊂7 显示出大量的肾脏和网状内皮积累。另一方面，化合物在体内的代谢产生了一种假定为（64）Cu-环十四烷-四精氨酸络合物的代谢产物，也在循环血液中保留了很长时间，从而阻止了肿瘤成像的更好对比。
