Comparison of Three Dimeric 18F-AlF-NOTA-RGD Tracers
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RGD peptide-based radiotracers are well established as integrin αvβ3 imaging probes to evaluate tumor angiogenesis or tissue remodeling after ischemia or infarction. In order to optimize the labeling process and pharmacokinetics of the imaging probes, we synthesized three dimeric RGD peptides with or without PEGylation and performed in vivo screening.
Radiolabeling was achieved through the reaction of F-18 aluminum–fluoride complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Three imaging probes were synthesized as 18F-AlF-NOTA-E[c(RGDfK)]2, 18F-AlF-NOTA-PEG4-E[c(RGDfK)]2, and 18F-AlF-NOTA-E[PEG4-c(RGDfk)]2. The receptor binding affinity was determined by competitive cell binding assay, and the stability was evaluated by mouse serum incubation. Tumor uptake and whole body distribution of the three tracers were compared through direct tissue sampling and PET quantification of U87MG tumor-bearing mice.
All three compounds remained intact after 120 min incubation with mouse serum. They all had a rapid and relatively high tracer uptake in U87MG tumors with good target-to-background ratios. Compared with the other two tracers, 18F-AlF-NOTA-E[PEG4-c(RGDfk)]2 had the highest tumor uptake and the lowest accumulation in the liver. The integrin receptor specificity was confirmed by co-injection of unlabeled dimeric RGD peptide.
The rapid one-step radiolabeling strategy by the complexation of 18F-aluminum fluoride with NOTA-peptide conjugates was successfully applied to synthesize three dimeric RGD peptides. Among the three probes developed, 18F-AlF-NOTA-E[PEG4-c(RGDfk)]2 with relatively low liver uptake and high tumor accumulation appears to be a promising candidate for further translational research.
Key wordsNOTA Arginine–glycine–aspartic acid (RGD) PET Integrin αvβ3 Aluminum–fluoride complex
This work was supported in part by the National Basic Research Program of China (973 Program) (No. 2013CB733800, 2013CB733802, 2014CB744503), the National Science Foundation of China (NSFC) (81201129, 81371596, 51373144 and 81101068), and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH).
Conflict of Interest
The authors declare that they have no conflicts of interest.