One-Step (18)F Labeling of Non-Peptidic Bivalent Integrin α(v)β(3) Antagonist for Cancer Imaging

[Image: see text] A rapid one-step (18)F labeling reaction with fluoridealuminum complex, which is based on chelation chemistry, has received a surge of interest for (18)F radiolabeling of peptides. In this study, a non-peptidic bivalent integrin α(v)β(3) antagonist (bivalent-IA) was conjugated with 1,4,7-triazacyclononane-1,4-diiacetic acid (NODA). A novel (18)F labeled radiotracer, (18)F-bivalent-IA, was developed via one step (18)F–AlF/NODA chelation reaction in aqueous phase with high radiochemical yield (65–75%, decay corrected) and good specific activity (750–850 mCi/μmol). The tumor integrin targeting efficiency and in vivo pharmacokinetic profile of (18)F-bivalent-IA were evaluated in U-87 MG (integrin positive) and MDA-MB-231 (integrin negative) models by small-animal PET/CT scan followed by a biodistribution study. The PET/CT and ROI results showed high tumor uptake of (18)F-bivalent-IA in U-87 MG tumor-bearing mice from 5 to 120 min p.i. with good contrast, and the U-87 MG tumor uptake values (6.35 ± 0.67%ID/g, at 1 h p.i.) were 6 times higher than those of MDA-MB-231 tumor (1.05 ± 0.12%ID/g, at 1 h p.i.) (P < 0.0001) which correlated with the integrin α(v)β(3) expression in tumor tissues confirmed by immunohistochemistry. Co-injection of the (18)F-bivalent-IA with 6 nmol (6 μg) of nonradioactive bivalent-IA effectively blocked tumor uptake demonstrating the integrin α(v)β(3)-specificity. In conclusion, the first (18)F labeled non-peptidic bivalent integrin α(v)β(3) targeting radiotracer, (18)F-bivalent-IA, was developed and proved to be a highly potent and specific PET radiopharmaceutical for noninvasive imaging of integrin α(v)β(3), which plays a critical role in tumor angiogenesis and metastasis.