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

Introduction: The aim of this study was to synthesize and perform a side-by-side comparison of two new tumor-angiogenesis PET tracers Ga-68-NODAGA-E[c(RGDyK)](2) and Cu-64-NODAGA-E[c(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. Methods: A Ge-68/Ga-68 generator was used for the synthesis of Ga-68-NODAGA-E[c(RGDyK)](2). Ga-68 and Cu-64 labeled NODAGA-E[c(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 al/133 target specificity was shown by blocking with cold NODAGA-E[c(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. Results: Ga-68-NODAGA-E[c(RGDyK)](2) was synthesized with a radiochemical purity of 89%-99% and a specific activity (SA) of 16-153 MBq/nmol. Cu-64-NODAGA-E[c(RGDyK)](2) had a purity of 92%-99% and an SA of 6478 MBq/nmol. Both tracers showed similar uptake in xenograft tumors 1 h after injection (U87MG: 2.23 vs. 2.31%1D/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 IAN was estimated. Conclusion: Ga-68-NODAGA-E[c(RGDyK)](2) and Cu-64-NODAGA-E[c(RGDyK)](2) can be easily synthesized and are both promising candidates for PET imaging of integrin avi33 positive tumor cells. Ga-68-NODAGA-E [c(RGDyK)](2) showed slightly more stable tumor retention. With the advantage of in-house commercially (68) Ge/Ga-68 generators, Ga-68-NODAGA-E[c(RGDyK))(2) may be the best choice for future clinical PET imaging in humans. (C) 2014 Elsevier Inc. All rights reserved.