68Ga-labeled cyclic RGD dimers with Gly3 and PEG4 linkers: promising agents for tumor integrin αvβ3 PET imaging

Purpose Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides have great potential for the early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response. 18 F-labeled RGD analogs ([ 18 F]-AH111585 and [ 18 F]Galacto-RGD) have been investigated in clinical trials for positron emission tomography (PET) imaging of integrin expression in cancer patients. To develop new RGD radiotracers with higher tumor accumulation, improved in vivo kinetics, easy availability and low cost, we developed two new RGD peptides and labeled them with generator-eluted 68 Ga (t 1/2 = 68 min) for PET imaging of integrin α v β 3 expression in tumor xenograft models. Materials and methods The two new cyclic RGD dimers, E[PEG 4 -c(RGDfK)] 2 (P 4 -RGD2, PEG 4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly 3 -c(RGDfK)] 2 (G 3 -RGD2, G 3 = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for 68 Ga labeling. The microPET imaging and biodistribution of the 68 Ga labeled RGD tracers were investigated in integrin α v β 3 -positive tumor xenografts. Results The new RGD dimers with the Gly 3 and PEG 4 linkers showed higher integrin α v β 3 binding affinity than no-linker RGD dimer (RGD2). NOTA-G 3 -RGD2 and NOTA-P 4 -RGD2 could be labeled with 68 Ga within 30 min with higher purity (>98%) and specific activity (8.88–11.84 MBq/nmol). Both 68 Ga-NOTA-P 4 -RGD2 and 68 Ga-NOTA-G 3 -RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than 68 Ga-NOTA-RGD2. Conclusion Because of their high affinity, high specificity and excellent pharmacokinetic properties, further investigation of the two novel RGD dimers for clinical PET imaging of integrin α v β 3 expression in cancer patients is warranted.