One-step radiosynthesis of 18F-AlF-NOTA-RGD2 for tumor angiogenesis PET imaging

Purpose One of the major obstacles of the clinical translation of F-18-labeled arginine-glycine-aspartic acid (RGD) peptides has been the laborious multistep radiosynthesis. In order to facilitate the application of RGD-based positron emission tomography (PET) probes in the clinical setting we investigated in this study the feasibility of using the chelation reaction between (AlF)-F-18 and a macrocyclic chelator-conjugated dimeric RGD peptide as a simple one-step F-18 labeling strategy for development of a PET probe for tumor angiogenesis imaging. Methods Dimeric cyclic peptide E[c(RGDyK)](2) (RGD(2)) was first conjugated with a macrocyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the resulting bioconjugate NOTA-RGD(2) was then radiofluorinated via (AlF)-F-18 intermediate to synthesize F-18-AlF-NOTA-RGD(2). Integrin binding affinities of the peptides were assessed by a U87MG cell-based receptor binding assay using I-125-echistatin as the radioligand. The tumor targeting efficacy and in vivo profile of F-18-AlF-NOTA-RGD(2) were further evaluated in a subcutaneous U87MG glioblastoma xenograft model by microPET and biodistribution. Results NOTA-RGD(2) was successfully F-18-fluorinated with good yield within 40 min using the (AlF)-F-18 intermediate. The IC50 of F-19-AlF-NOTA-RGD(2) was determined to be 46 +/- 4.4 nM. Quantitative microPET studies demonstrated that F-18-AlF-NOTA-RGD(2) showed high tumor uptake, fast clearance from the body, and good tumor to normal organ ratios. Conclusion NOTA-RGD(2) bioconjugate has been successfully prepared and labeled with (AlF)-F-18 in one single step of radiosynthesis. The favorable in vivo performance and the short radiosynthetic route of F-18-AlF-NOTA-RGD(2) warrant further optimization of the probe and the radiofluorination strategy to accelerate the clinical translation of F-18-labeled RGD peptides.