Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of α V β 3 Integrin Activity

Sci Rep. 2017 Jun 9;7(1):3185. doi: 10.1038/s41598-017-03224-8.


Cyclic peptides containing the Arg-Gly-Asp (RGD) sequence have been shown to specifically bind the angiogenesis biomarker α V β 3 integrin. We report the synthesis, chemical characterization, and biological evaluation of two novel dimeric cyclic RGD-based molecular probes for the targeted imaging of α V β 3 activity (a radiolabeled version, 64Cu-NOTA-PEG4-cRGD2, for PET imaging, and a fluorescent version, FITC-PEG4-cRGD2, for in vitro work). We investigated the performance of this probe at the receptor, cell, organ, and whole-body levels, including its use to detect diabetes associated impairment of ischemia-induced myocardial angiogenesis. Both versions of the probe were found to be stable, demonstrated fast receptor association constants, and showed high specificity for α V β 3 in HUVECs (K d ~ 35 nM). Dynamic PET-CT imaging indicated rapid blood clearance via kidney filtration, and accumulation within α V β 3-positive infarcted myocardium. 64Cu-NOTA-PEG4-cRGD2 demonstrated a favorable biodistribution, slow washout, and excellent performance with respect to the quality of the PET-CT images obtained. Importantly, the ratio of probe uptake in infarcted heart tissue compared to normal tissue was significantly higher in non-diabetic rats than in diabetic ones. Overall, our probes are promising agents for non-invasive quantitative imaging of α V β 3 expression, both in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Copper Radioisotopes / pharmacology
  • Dimerization
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds, 1-Ring
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors
  • Integrin alphaVbeta3 / genetics*
  • Kidney / drug effects
  • Kidney / metabolism
  • Mice
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / pathology
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Peptides, Cyclic / chemical synthesis
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Positron-Emission Tomography
  • Rats
  • Tissue Distribution / drug effects


  • Copper Radioisotopes
  • Copper-64
  • Heterocyclic Compounds
  • Heterocyclic Compounds, 1-Ring
  • Integrin alphaVbeta3
  • Oligopeptides
  • Peptides, Cyclic
  • cyclic arginine-glycine-aspartic acid peptide
  • 1,4,7-triazacyclononane-N,N',N''-triacetic acid
  • arginyl-glycyl-aspartic acid