64Cu-labeled CB-TE2A and Sar conjugated RGD peptide analogs for targeting angiogenesis: Comparison of their biological activity

摘要: 233 Objectives: The αvβ3 integrin is a cell adhesion molecule known to be involved in stages of angiogenesis and metastasis. In this study, the chelators CB-TE2A Sarcophagine (Sar) were conjugated RGD peptide analogs cyclic RGDyK RGDfD biological properties 64Cu labeled peptides compared. Methods: CB-TE2A-c(RGDyK) Sar-c(RGDfD) with 0.1 M NH4OAc (pH = 8) at 95 °C 25 °C, respectively, for 1 h. PET biodistribution studies carried out on M21 (αvβ3-positive) M21L (αv-negative) melanoma-bearing mice 1, 2, 4 24h post injection (p.i.). Binding affinity Cu-chelator-RGD integrins was determined by competitive binding assay. Results: Biological showed higher tumor uptake compared (e.g. 4h p.i., 64Cu-CB-TE2A-c(RGDyK): 1.66±0.8 (M21) vs. 0.84±0.41 %ID/g (M21L), p=0.04). Tumor uptakes 64Cu-CB-TE2A-c(RGDyK) are than those 64Cu-Sar-c(RGDfD)(e.g., 1h 2.98±0.90 64Cu-Sar-c(RGDfD): 1.51±0.53 %ID/g, p=0.01). These differences not due differing affinities, since similar values obtained agents from assays (IC50: Cu-CB-TE2A-c(RGDyK): 6.0 nM Cu-Sar-c(RGDfD): 4.8 c(RGDyK): 3.7 nM). Compared Cu-CB-TE2A-c(RGDyK), which has longer lysine linker, Cu-Sar-c(RGDfD) closer site peptide, potentially causing partial demetallation Cu complex. slower liver clearance 64Cu-Sar-c(RGDfD) (2.63±0.53 (2h p.i.) 2.24±0.41 (24h p.i.), p=NS) (2.53±0.89 0.84±0.17 p=0.05) further evidence demetallation. Administration c(RGDyK) as block significantly reduced indicating receptor-specific accumulation. Conclusions: Both potential candidates imaging angiogenesis. For Sar-c(RGDfD), linker may needed between Cu-chelate moiety achieve optimal vivo uptake. Research Support (if any): NCI grants R24 CA86307 R01 CA93375