New Glucocyclic RGD Dimers for Positron Emission Tomography Imaging of Tumor Integrin Receptors

Most studies of radiolabeled arginine-glycine-aspartic acid (RGD) peptides have shown in vitro affinity for integrin α_νβ₃, allowing for the targeting of receptor-positive tumors in vivo. However, major differences have been found in the pharmacokinetic profiles of different radiolabeled RGD peptide analogs. The purposes of this study were to prepare ⁶⁴Cu-DOTA-gluco-E[c(RGDfK)]₂ (R8), ⁶⁴Cu-NOTA-gluco-E[c(RGDfK)]₂ (R9), and ⁶⁴Cu-NODAGA-gluco-E[c(RGDfK)]₂ (R10) and compare their pharmacokinetics and tumor imaging properties using small-animal positron emission tomography (PET). All three compounds were produced with high specific activity within 10 minutes. The IC₅₀ values were similar for all the substances, and their affinities were greater than that of c(RGDyK). R8, R9, and R10 were stable for 24 hours in human and mouse serums and showed high uptake in U87MG tumors with high tumor-to-blood ratios. Compared to the control, a cyclic RGD peptide dimer without glucosamine, R10, showed low uptake in the liver. Because of their good imaging qualities and improved pharmacokinetics, ⁶⁴Cu-labeled dimer RGD conjugates (R8, R9, and R10) may have potential applications as PET radiotracers. R9 (NOTA) with highly in vivo stability consequentially showed an improved PET tumor uptake than R8 (DOTA) or R10 (NODAGA).