Hultsch Christina, Pawelke Beate, Bergmann Ralf, Wuest Frank
Institute of Radiopharmacy, Research Center Rossendorf, Germany.
Bioorg Med Chem. 2006 Sep 1;14(17):5913-20. doi: 10.1016/j.bmc.2006.05.024. Epub 2006 Jun 2.
Neurotensin(8-13) is a hexapeptide with subnanomolar affinity to the neurotensin receptor 1 which is expressed with high incidence in several human tumor entities. Thus, radiolabeled neurotensin(8-13) might be used for tumor targeting. However, its application is limited by insufficient metabolic stability. The present study aims at improving metabolic stability by the synthesis of multimeric neurotensin(8-13) derivatives rather than commonly employed chemical modifications of the peptide itself. Thus, different dimeric and tetrameric peptides carrying C- or N-terminal attached neurotensin(8-13) moieties have been synthesized and their binding affinity toward the neurotensin receptor has been determined. The results demonstrate that branched compounds containing neurotensin(8-13) attached via its C-terminus only show low receptor affinities, whilst derivatives with neurotensin(8-13) attached via the N-terminus show IC50 values in the nanomolar range. Moreover, within the multimeric neurotensin(8-13) derivatives with neurotensin(8-13) attached via the N-terminus an increasing number of branching units lead to higher binding affinities toward the neurotensin receptor.
神经降压素（8 - 13）是一种六肽，对神经降压素受体1具有亚纳摩尔亲和力，该受体在多种人类肿瘤实体中高表达。因此，放射性标记的神经降压素（8 - 13）可用于肿瘤靶向。然而，其应用受到代谢稳定性不足的限制。本研究旨在通过合成多聚体神经降压素（8 - 13）衍生物而非常用的肽本身化学修饰来提高代谢稳定性。因此，已合成了不同的带有C端或N端连接神经降压素（8 - 13）部分的二聚体和四聚体肽，并测定了它们对神经降压素受体的结合亲和力。结果表明，仅通过其C端连接神经降压素（8 - 13）的支链化合物显示出低受体亲和力，而通过N端连接神经降压素（8 - 13）的衍生物显示出纳摩尔范围内的IC50值。此外，在通过N端连接神经降压素（8 - 13）的多聚体神经降压素（8 - 13）衍生物中，分支单元数量增加会导致对神经降压素受体的结合亲和力更高。
