Oligoprolin als molekulares Gerüst für multivalente, peptidische Tumor-Targeting Liganden

Peptidic, radiolabelled ligands that bind to receptors overexpressed on tumor cells are attractive for molecular imaging and therapy. The gastrin-releasing peptide receptor (GRP-R) is overexpressed on prostate- and breast tumors and is therefore an interesting target. The GRP-R can be targeted both with agonist and antagonists to achieve an enrichment of radioligands in the tumor. Herein we present a novel approach towards multi- and heterovalent radiotracers for tumor targeting. We are especially interested in combining an agonist and an antagonist on a radiolabeled rigid scaffold in defined distances. Such hybrid ligands may combine the potency of antagonists (high uptake due to more binding sites) with the properties of agonists (slow washout due to internalization) and therefore lead to higher tumor uptake. --
In our approach azido-functionalized oligoprolines are used as helical, conformationally well-defined scaffolds to display peptidic targeting vectors. As targeting vectors, bombesin agonists and antagonists with a high affinity towards gastrin releasing peptide receptors (GRP-R) are employed. Conjugation to the scaffold has been achieved via copper catalyzed "click chemistry". The modular synthesis of the molecules is performed on solid support. Additionally, a DOTA-chelator was introduced for labelling with different radiometals. --
A series of molecules, differing in type and composition of the targeting vectors has been synthesized. In vitro studies with 177Lu labelled ligands show excellent binding and high internalization of the novel hybride ligands. The experiments show, that the uptake depends on the distance between the two binding elements and that there is an optimal distance of 20 Å between the two recognition elements. PET images of mice with 68Ga labelled ligands demonstrate the high and specific uptake in the tumor. Biodistribution experiments showed that tumor uptake of the best hybrid ligand is much higher compared to established monovalent controls, and washout is slower. A hypothesis is presented which might explain the high uptake of the best hybride ligand.