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. 68Ga- and 18F-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 Ile12 by tert-butylglycine12 (Tle12) and N-terminal acylation. N-Methylation of either arginine, Arg8, or Arg9, combined with the Ile12/Tle12 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).