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

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).