Synthesis and biological evaluation of potent a v h 3 -integrin receptor antagonists

Introduction: avh3 Integrin is expressed in sprouting endothelial cells in growing tumors, whereas it is absent in quiescent blood vessels. In addition, various tumor cell types express avh3 integrin. avh3 Integrin, a transmembrane heterodimeric protein, binds to the arginine– glycine–aspartic acid (RGD) amino acid sequence of extracellular matrix proteins such as vitronectin and plays a pivotal role in invasion, proliferation and metastasis. Due to the selective expression of avh3 integrin in tumors, radiolabeled RGD peptides and peptidomimetics are attractive candidates for tumor targeting. Methods: A cyclic RGD peptide, a peptoid–peptide hybrid, an all-peptoid and a peptidomimetic compound were synthesized, conjugated with 1,4,7,10-tetraazadodecane-N,NV,NW,Nj-tetraacetic acid (DOTA) and radiolabeled with 111 In. Their in vitro and in vivo avh3-binding characteristics were determined. Results: IC50 values were 236 nM for DOTA-E-c(RGDfK), 219 nM for DOTA-peptidomimetic, N10 mM for DOTA-all-peptoid and 9.25 mM for the peptoid–peptide hybrid DOTA-E-c(nRGDfK). 111 In-labeled compounds, except for [ 111 In]DOTA-all-peptoid, showed specific uptake in human avh3-expressing tumors xenografted in athymic mice. Tumor uptake for [ 111 In]DOTA-E-c(RGDfK) was 1.73F0.4% ID/g (2 h postinjection) and that of [ 111 In]DOTA-peptidomimetic was 2.04F0.3% ID/g. Tumor uptake for the peptoid–peptide hybrid [ 111 In]DOTA-E-c(nRGDfK) was markedly lower (0.45F0.07% ID/g). The all-peptoid [ 111 In]DOTA-E-c(nRGnDnFnK) did not show