18F-Peptide probe for PET imaging of VEGF expression

Objectives Blocking vascular endothelial growth factor (VEGF) has been validated as an effective approach for cancer therapy and overexpression of VEGF in tumors is associated with a poor prognosis. Recently, the anti-VEGF mAb bevacizumab was radiolabeled with 89Zr and used to monitor VEGF expression in human ovarian tumor xenografts using PET [1]. However, due to the long plasma half-life of radiolabeled bevacizumab, seven days are required to achieve maximum contrast. Additionally, since the VEGF levels may be rapidly changing, the use of 89Zr-mAbs may not be suitable for imaging of acute VEGF levels.

Methods Since PET probes based on 18F-labeled peptides demonstrate fast clearance, optimal contrast can be achieved within a few hours allowing repeated daily imaging. Target specific 18F-peptides can be obtained by combinatorial drug discovery methods combined with high throughput PET [2].

Results Phage display library of peptides was screened against human VEGF and four peptides were identified with binding affinities to VEGF in the range 24-105 nM. The peptides were synthesized on solid phase and decorated with 4-pentynoic acid at the N-terminus, purified, and radiolabeled with 18F-PEG8-N3 using copper catalyzed alkyne-azide cycloaddition [3] with 21-45% RCY. The imaging properties of 18F-peptides were evaluated in human colon cancer model (HM7) and the peptide 18F-A3B provided the highest tumor uptake (0.85 ± 0.14 %ID/g, n = 3) with average tumor/blood and tumor/muscle ratios equal to 2.2 and 5.6 reached within 2 h post injection. The images obtained with 18F-A3B were comparable to images obtained using 89Zr-B20 (anti-VEGF mAb) and 89Zr-bevacizumab.

Conclusions In conclusion, we have developed a peptide based 18F-tracer for non-invasive PET of VEGF expression. [1] Nagengast WB et al J. Nucl. Med. 2007, 48, 1313 [2] Gagnon MKJ et al PNAS 2009, 106, 17904 [3] Gill HS et al J. Med. Chem. 2009, 52, 581