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

Purpose One of the major obstacles of the clinical translation of 18 F-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 Al 18 F and a macrocyclic chelator-conjugated dimeric RGD peptide as a simple one-step 18 F 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 Al 18 F intermediate to synthesize 18 F-AlF-NOTA-RGD 2 . Integrin binding affinities of the peptides were assessed by a U87MG cell-based receptor binding assay using 125 I-echistatin as the radioligand. The tumor targeting efficacy and in vivo profile of 18 F-AlF-NOTA-RGD 2 were further evaluated in a subcutaneous U87MG glioblastoma xenograft model by microPET and biodistribution. Results NOTA-RGD 2 was successfully 18 F-fluorinated with good yield within 40 min using the Al 18 F intermediate. The IC 50 of 19 F-AlF-NOTA-RGD 2 was determined to be 46 ± 4.4 nM. Quantitative microPET studies demonstrated that 18 F-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 Al 18 F in one single step of radiosynthesis. The favorable in vivo performance and the short radiosynthetic route of 18 F-AlF-NOTA-RGD 2 warrant further optimization of the probe and the radiofluorination strategy to accelerate the clinical translation of 18 F-labeled RGD peptides.