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

Due to its expression in various malignant tumors, the neurotensin receptor 1 (NTSR) has been suggested and explored as a target for tumor diagnosis and therapy. Animal model-based investigations of various radiolabeled NTSR ligands derived from the hexapeptide neurotensin(8-13) (NT(8-13)), e.g. Ga- and F-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 -methyl scan, replacing Ile by -butylglycine (Tle) and N-terminal acylation. -Methylation of either arginine, Arg, or Arg, combined with the Ile/Tle exchange, proved to be most favorable with respect to NTSR affinity ( < 2 nM) and stability in human plasma ( > 48 h), a valuable result regarding the development of radiopharmaceuticals derived from NT(8-13).