Modifications at Arg and Ile Give Neurotensin(8-13) Derivatives with High Stability and Retained NTS1 Receptor Affinity

Due to its expression in various malignant tumors, the neurotensin receptor 1 (NTS1R) has been suggested and explored as a target for tumor diagnosis and therapy. Animal model-based investigations of various radiolabeled NTS1R ligands derived from the hexapeptide neurotensin(8-13) (NT(8-13)), e.g. Ga-68- and F-18-labeled compounds for PET diagnostics, give rise to optimize such radiotracers for clinical use. As NT(8-13) is rapidly degraded in vivo; structural modifications are required in terms of increased metabolic stability. In this study, the stabilization of the peptide backbone of NT(8-13) against enzymatic degradation was systematically explored by performing an N-methyl scan, replacing Ile(12) by tert-butylglycine(12) (Tle(12)) and N-terminal acylation. N-Methylation of either arginine, Arg(8), or Arg(9), combined with the Ile(12)/Tle(12) exchange, proved to be most favorable with respect to NTS1R affinity (K-i < 2 nM) and stability in human plasma (t(1/2) > 48 h), a valuable result regarding the development of radiopharmaceuticals derived from NT(8-13).