Synthesis and biological evaluation of potent αvβ3-integrin receptor antagonists

Introduction: alpha(v)beta(3) 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 alpha(3)beta(3) integrin. alpha(v)beta(3) 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 alpha(v)beta(3) integrin in tumors, radiolabeled RGD peptides and peptidomimetis 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,N',N",N '''-tetraacetic acid (DOTA) and radiolabeled with In-111. Their in vitro and in vivo alpha(v)beta(3)-binding characteristics were determined. Results: IC50 values were 236 nM for DOTA-E-c(RGDfK), 219 nM for DOTA-peptidomimetic, > 10 mM for DOTA-all-peptoid and 9.25 mM for the peptoid-peptide hybrid DOTA-E-c(nRGDfK). In-111-labeled compounds, except for [In-111]DOTA-all-peptoid, showed specific uptake in human alpha(v)beta(3)-expressing tumors xenografted in athymic mice. Tumor uptake for [In-111]DOTA-E-c(RGDfK) was 1.73 +/- 0.4% ID/g (2 h postinjection) and that of [In-111]DOTA-peptidornimetic was 2.04 +/- 0,3% ID/g. Tumor uptake for the peptoid-peptide hybrid [In-111]DOTA-E-c(nRGDfK) was markedly lower (0.45 +/- 0.07% ID/g). The all-peptoid [In-111]DOTA-E-c(nRGnDnFnK) did not show specific uptake in tumors (0.11 +/- 0.04% ID/g). Conclusions: The peptidomimetic compound and the cyclic RGD peptide have a high affinity for alpha(v)beta(3) integrin, and these compounds have better tumor-targeting characteristics than the peptoid-peptide hybrid and the all-peptoid. (c) 2006 Elsevier Inc. All rights reserved.