Biological evaluation of a novel stable peptide PET molecular probe [F]AlF-NOTA-VAP targeting to tumor cell surface GRP78.

Backgrounds: Glucose-Regulated Protein 78 (GRP78) is an attractive anticancer target for its selective anchoring on the surface of tumor cells and cancer endothelial cells rather than normal cells. Cell-surface GRP78 overexpression of tumor indicates that GRP78 is a crucial target for relative tumor imaging and clinical treatment. Herein, we report the design and preclinical evaluation of a new D peptide ligand [F]AlF-NOTA-VAP recognizing GRP78 expressed on the cell surface of breast cancer.

Methods: Radiochemical synthesis of [F]AlF-NOTA-VAP was achieved via a one-pot labeling process by heating NOTA-VAP in the presence of in situ prepared [F]AlF for 15 min at 110 °C and purified through HPLC.

Results: The radiotracer showed high in vitro stability in rat serum at 37 °C over 3 h. Both biodistribution studies and in vivo micro-PET/CT imaging studies in BALB/c mice bearing 4 T1 tumor showed [F]AlF-NOTA-VAP had a rapid and high uptake in tumor, as well as a long residence time. The high hydrophilicity of the radiotracer enables its fast clearance from most normal tissues and thus improves the tumor-to-normal tissue ratios (4.40 at 60 min) which is better than [F]FDG (1.31 at 60 min). Pharmacokinetic studies showed the average in vivo mean residence time of the radiotracer was just 0.6432 h and indicated that this hydrophilic radiotracer was quickly eliminated from the body to reduce the distribution of non-target tissues.

Conclusions: These results suggest that [F]AlF-NOTA-VAP is a very promising PET probe for tumor-specific imaging of cell-surface GRP78-positive tumor.