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.