Comparison of two new angiogenesis PET tracers 68Ga-NODAGA-E[c(RGDyK)]2 and 64Cu-NODAGA-E[c(RGDyK)]2; in vivo imaging studies in human xenograft tumors

IntroductionThe aim of this study was to synthesize and perform a side-by-side comparison of two new tumor-angiogenesis PET tracers ⁶⁸Ga-NODAGA-Ec(RGDyK)]₂ and ⁶⁴Cu-NODAGA-Ec(RGDyK)]₂ in vivo using human xenograft tumors in mice. Human radiation burden was estimated to evaluate potential for future use as clinical PET tracers for imaging of neo-angiogenesis.MethodsA ⁶⁸Ge/⁶⁸Ga generator was used for the synthesis of ⁶⁸Ga-NODAGA-Ec(RGDyK)]₂. ⁶⁸Ga and ⁶⁴Cu labeled NODAGA-Ec(RGDyK)]₂ tracers were administrated in nude mice bearing either human glioblastoma (U87MG) or human neuroendocrine (H727) xenograft tumors. PET/CT scans at 3 time points were used for calculating the tracer uptake in tumors (%ID/g), integrin α_Vβ₃ target specificity was shown by blocking with cold NODAGA-Ec(RGDyK)]₂, and biodistribution in normal organs were also examined. From biodistribution data in mice human radiation-absorbed doses were estimated using OLINDA/EXM software.Results⁶⁸Ga-NODAGA-Ec(RGDyK)]₂ was synthesized with a radiochemical purity of 89%–99% and a specific activity (SA) of 16–153 MBq/nmol. ⁶⁴Cu-NODAGA-Ec(RGDyK)]₂ had a purity of 92%–99% and an SA of 64–78 MBq/nmol.Both tracers showed similar uptake in xenograft tumors 1 h after injection (U87MG: 2.23 vs. 2.31%ID/g; H727: 1.53 vs. 1.48%ID/g). Both RGD dimers showed similar tracer uptake in non-tumoral tissues and a human radiation burden of less than 10 mSv with an administered dose of 200 MBq was estimated.Conclusion⁶⁸Ga-NODAGA-Ec(RGDyK)]₂ and ⁶⁴Cu-NODAGA-Ec(RGDyK)]₂ can be easily synthesized and are both promising candidates for PET imaging of integrin α_Vβ₃ positive tumor cells. ⁶⁸Ga-NODAGA-Ec(RGDyK)]₂ showed slightly more stable tumor retention. With the advantage of in-house commercially ⁶⁸Ge/⁶⁸Ga generators, ⁶⁸Ga-NODAGA-Ec(RGDyK)]₂ may be the best choice for future clinical PET imaging in humans.