Abstract
Neurotensin (NT) is a tridecapeptide, which was first isolated from bovine hypothalamus.[1] The C-terminal fragment NT[8-13] is the minimal bioactive sequence, which induces antinociceptive action and other physiological side effects such as hypothermia and hypotension by interaction with its receptors. Among the NT receptor subtypes, Sarret et al. showed that the selectivity towards NTS2 is fundamental to exert an analgesic activity without unwanted effects.[2] Several structure-activity relationship studies point out the importance of Tyrosine residue in position 11 to drive the selectivity NTS2/NTS1. Based on these results, we developed several NT[8-13] analogues using different approaches including unnatural amino acid incorporation[3] and peptide bond modification in order to improve their affinity, their stability and their activity. In addition, since the interaction between neurotensin and its receptor NTS1 has been clarified by crystallization with the NT[8-13] ligand,[4] we explored the differences between NTS1 and NTS2 by molecular modeling to understand the rule of this selectivity.[5]On the other hand, recent studies demonstrated that NTS1 is overexpressed in breast cancer, pancreatic adenocarcinomas, prostate and stomach cancers among others.[6] In this context, we have synthesized new radiolabeled NT[8-13] analogues, highly selective towards NTS1 with an increased plasmatic stability and lipophilicity for imaging and therapy of those tumors.[7]