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Bioconjug Chem. 2014 Mar 19;25(3):489-500. doi: 10.1021/bc4004662. Epub 2014 Feb 25.

PESIN multimerization improves receptor avidities and in vivo tumor targeting properties to GRPR-overexpressing tumors.

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Department of Nuclear Medicine, University Hospital Munich, Ludwig Maximilians-University Munich , 81377 Munich, Germany.


The gastrin releasing peptide receptor (GRPR), being overexpressed on several tumor types, represents a promising target for specific noninvasive in vivo tumor imaging using positron emission tomography. Many of the radiolabeled bombesin analogs being applied in tumor imaging, however, suffer from shortcomings such as limited in vivo stability and poor tumor to background ratios. These obstacles can be overcome by peptide multimerization, as this approach results in constructs comprising several copies of the same peptide, thus retaining the ability to specifically bind to the target structure even if one peptide is cleaved. Furthermore, peptide multimers can result in increased binding avidities to the target, which can entail higher absolute tumor uptakes and also tumor to background levels. We therefore synthesized monomers and multimers of the peptide PESIN on dendrimer scaffolds comprising linkers of different lengths. The monomers/multimers were functionalized with the chelator NODAGA, efficiently radiolabeled with (68)Ga and evaluated in vitro regarding their GRPR binding affinity. The results show that shorter distances between the peptide moieties result in substantially higher binding affinities/avidities of the monovalent/multivalent PESIN ligands to the GRPR. Furthermore, the bivalent ligands gave the best results in terms of binding avidity, achieving a 2.5-fold increase in avidity compared to the respective monomer. Moreover, the most potent bivalent ligand showed an about 2-fold higher absolute tumor uptake and twice as high tumor-to-background ratios than the monomeric reference DOTA-PESIN in an initial animal PET study in tumor-bearing mice. Thus, besides high avidities, multivalency also positively influences the in vivo pharmacokinetics of peptide multimers.

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