microPET of Tumor Integrin  v 3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

Abstract

In vivo imaging of a v b 3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin a v b 3 -binding affinity due to the polyvalency effect. Here we report an example of 18 F-labeled tetrameric RGD peptide for PET of a v b 3 expression in both xenograft and spontaneous tumor models. Methods: The tetrameric RGD peptide EfE[c(RGDyK)] 2 g 2 was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate a-amino group. NH 2 -mini-PEG-EfE[c(RGDyK)] 2 g 2 (PRGD4) was labeled with 18 F via the N-succinimidyl-4-18 F-fluorobenzoate ( 18 F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18 F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies. Results: The decay-corrected radiochemical yield for 18 F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from 18 F-F 2 . The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18 F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18 F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). Conclusion: The tetrameric RGD peptide tracer 18 F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin a v b 3 expression in cancer and other angiogenesis related diseases.

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

“…60 Cu-ATSM imaging showed therapy responders had lower tumor-to-normal tissue compared to FDG imaging, while non-responders showed high tumor-to-normal tissue ratios in both [105]. Studies comparing 64 Cu-ATSM with 18 F-FMISO and 18 F-FDG in vivo are also reported. The regional distribution of 18 F-FMISO at 2 h correlates well with the distribution of 64 Cu-ATSM at 10 min or 24 h in 9 L gliosarcoma tumors, whereas a poor correlation existed between 64 Cu-ATSM and 18 F-FDG at 10 min [106].…”

“…However, due to the in vivo stability, cyclic RGD is more favorable than linear RGD and has been well studied by labeling with various radioisotopes [62]. 18 F-Galacto-c(RGDfK), radiolabeled PEGylated RGD peptide, F-18-labeled RGD dimer [63], tetramer [64], Cu-64-labeled tetramer and octamer [65], and Ga-68-labeled cyclic RGD dimers [66,67] are all reported in searching for improved pharmacokinetic behaviors, including better tumor uptake and a prolonged retention pattern (Fig. 3).…”

“…64 Cu-DOTA-labeled knottin peptide 2.5D had higher binding affinity to integrin and more favorable tissue distribution, as indicated by lower liver uptake compared to 64 Cu-DOTA-c(RGDyK) [77]. Furthermore, F-18-labeled knottin, also reported as 18 F-fluorobenzoaldehyde (FB)-2.5D, had high gallbladder and kidney accumulation and fast tumor clearance, which indicated the poor stability in vivo.…”

“…The 121 , which has a correlation of tumor uptake and VEGFR expression [81]. Furthermore, VEGF DEE , a mutant of VEGF 121 , is labeled by 64 Cu as 64 Cu-DOTA-VEGFDEE, and showed even better VEGFR-2 specificity than the wildtype 64 Cu-DOTA-VEGF 121 [82].…”

“…Studies comparing 64 Cu-ATSM with 18 F-FMISO and 18 F-FDG in vivo are also reported. The regional distribution of 18 F-FMISO at 2 h correlates well with the distribution of 64 Cu-ATSM at 10 min or 24 h in 9 L gliosarcoma tumors, whereas a poor correlation existed between 64 Cu-ATSM and 18 F-FDG at 10 min [106]. Lewis et al [107] reported that studies of 64 Cu-ATSM in ten cervical cancer patients obtained high quality images of tumor hypoxia.…”