68Ga-labeled multimeric RGD peptides for microPET imaging of integrin αvβ3 expression

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We and others have reported that 18F- and 64Cu-labeled arginine-glycine-aspartate (RGD) peptides allow positron emission tomography (PET) quantification of integrin αvβ3 expression in vivo. However, clinical translation of these radiotracers is partially hindered by the necessity of cyclotron facility to produce the PET isotopes. Generator-based PET isotope 68Ga, with a half-life of 68 min and 89% positron emission, deserves special attention because of its independence of an onsite cyclotron. The goal of this study was to investigate the feasibility of 68Ga-labeled RGD peptides for tumor imaging.


Three cyclic RGD peptides, c(RGDyK) (RGD1), E[c(RGDyK)]2 (RGD2), and E{E[c(RGDyK)]2}2 (RGD4), were conjugated with macrocyclic chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with 68Ga. Integrin affinity and specificity of the peptide conjugates were assessed by cell-based receptor binding assay, and the tumor targeting efficacy of 68Ga-labeled RGD peptides was evaluated in a subcutaneous U87MG glioblastoma xenograft model.


U87MG cell-based receptor binding assay using 125I-echistatin as radioligand showed that integrin affinity followed the order of NOTA-RGD4 > NOTA-RGD2 > NOTA-RGD1. All three NOTA conjugates allowed nearly quantitative 68Ga-labeling within 10 min (12-17 MBq/nmol). Quantitative microPET imaging studies showed that 68Ga-NOTA-RGD4 had the highest tumor uptake but also prominent activity accumulation in the kidneys. 68Ga-NOTA-RGD2 had higher tumor uptake (e.g., 2.8 ± 0.1%ID/g at 1 h postinjection) and similar pharmacokinetics (4.4 ± 0.4 tumor/muscle ratio, 2.0 ± 0.1 tumor/liver ratio, and 1.1 ± 0.1 tumor/kidney ratio) compared with 68Ga-NOTA-RGD1.


The dimeric RGD peptide tracer 68Ga-NOTA-RGD2 with good tumor uptake and favorable pharmacokinetics warrants further investigation for potential clinical translation to image integrin αvβ3.

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