title: Synthesis and biological evaluation of potent alphavbeta3-integrin receptor antagonists.
abstract: BACKGROUND
  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(v)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 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,N',N'',N'''-tetraacetic acid (DOTA) and radiolabeled with (111)In. Their in vitro and in vivo alpha(v)beta(3)-binding characteristics were determined.
  
  
  RESULTS
  IC(50) 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). (111)In-labeled compounds, except for [(111)In]DOTA-all-peptoid, showed specific uptake in human alpha(v)beta(3)-expressing tumors xenografted in athymic mice. Tumor uptake for [(111)In]DOTA-E-c(RGDfK) was 1.73+/-0.4% ID/g (2 h postinjection) and that of [(111)In]DOTA-peptidomimetic was 2.04+/-0.3% ID/g. Tumor uptake for the peptoid-peptide hybrid [(111)In]DOTA-E-c(nRGDfK) was markedly lower (0.45+/-0.07% ID/g). The all-peptoid [(111)In]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.
authors.affiliation: Department of Nuclear Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. clemens.decristoforo@uibk.ac.at <clemens.decristoforo@uibk.ac.at>
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.forename: John A W
authors.initials: JA
authors.lastname: Kruijtzer
authors.forename: Cathelijne
authors.initials: C
authors.lastname: Frielink
authors.forename: Annemieke C
authors.initials: AC
authors.lastname: Soede
authors.forename: Hans W
authors.initials: HW
authors.lastname: Hilbers
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
authors.forename: Frans H M
authors.initials: FH
authors.lastname: Corstens
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D004355:Drug Stability; D005260:Female; D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D007205:Indium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; C047981:arginyl-glycyl-aspartic acid