Fiche publication
Date publication
septembre 2015
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr VALVERDE Ibai
Tous les auteurs :
Valverde IE, Vomstein S, Fischer CA, Mascarin A, Mindt TL
Lien Pubmed
Résumé
Novel backbone-modified radiolabeled analogs based on the tumor targeting peptide bombesin were synthesized and fully evaluated in vitro and in vivo. We have recently introduced the use of 1,4-disubstituted 1,2,3-triazoles as metabolically stable trans-amide bond surrogates in radiolabeled peptides in order to improve their tumor targeting. As an extension of our approach, we now report several backbone-modified analogs of the studied bombesin peptide bearing multiple triazole substitutions. We investigated the effect of the modifications on several biological parameters including the internalization of the radiopeptidomimetics into tumor cells, their affinity toward the gastrin releasing peptide receptor (GRPr), metabolic stability in blood plasma, and biodistribution in mice bearing GRPr-expressing xenografts. The backbone-modified radiotracers exhibited a significantly increased resistance to proteolytic degradation. In addition, some of the radiopeptidomimetics retained a nanomolar affinity toward GRPr, resulting in an up to 2-fold increased tumor uptake in vivo in comparison to a (all amide bond) reference compound.
Mots clés
Amides, chemistry, Animals, Bombesin, analogs & derivatives, Cell Line, Tumor, Heterografts, Humans, Lutetium, Mice, Nude, Neoplasm Transplantation, Peptide Fragments, chemistry, Peptidomimetics, chemistry, Proteolysis, Radiopharmaceuticals, chemistry, Receptors, Bombesin, metabolism, Structure-Activity Relationship, Tissue Distribution, Triazoles, chemistry
Référence
J. Med. Chem.. 2015 Sep 24;58(18):7475-84
