Synthesis and evaluation of novel multimeric neurotensin(8-13) analogs

Neurotensin(8–13) is a hexapeptide with subnanomolar affinity to the neurotensin receptor 1 which is expressed with high incidence in several human tumor entities. Thus, radiolabeled neurotensin(8–13) might be used for tumor targeting. However, its application is limited by insufficient metabolic stability. The present study aims at improving metabolic stability by the synthesis of multimeric neurotensin(8–13) derivatives rather than commonly employed chemical modifications of the peptide itself. Thus, different dimeric and tetrameric peptides carrying C- or N-terminal attached neurotensin(8–13) moieties have been synthesized and their binding affinity toward the neurotensin receptor has been determined. The results demonstrate that branched compounds containing neurotensin(8–13) attached via its C-terminus only show low receptor affinities, whilst derivatives with neurotensin(8–13) attached via the N-terminus show IC₅₀ values in the nanomolar range. Moreover, within the multimeric neurotensin(8–13) derivatives with neurotensin(8–13) attached via the N-terminus an increasing number of branching units lead to higher binding affinities toward the neurotensin receptor.