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

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Abstract

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. 18F-labeled RGD analogs ([18F]-AH111585 and [18F]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 68Ga (t1/2 = 68 min) for PET imaging of integrin αvβ3 expression in tumor xenograft models.

Materials and methods

The two new cyclic RGD dimers, E[PEG4-c(RGDfK)]2 (P4-RGD2, PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly3-c(RGDfK)]2 (G3-RGD2, G3 = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for 68Ga labeling. The microPET imaging and biodistribution of the 68Ga labeled RGD tracers were investigated in integrin αvβ3-positive tumor xenografts.

Results

The new RGD dimers with the Gly3 and PEG4 linkers showed higher integrin αvβ3 binding affinity than no-linker RGD dimer (RGD2). NOTA-G3-RGD2 and NOTA-P4-RGD2 could be labeled with 68Ga within 30 min with higher purity (>98%) and specific activity (8.88–11.84 MBq/nmol). Both 68Ga-NOTA-P4-RGD2 and 68Ga-NOTA-G3-RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than 68Ga-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 αvβ3 expression in cancer patients is warranted.