title: One-step (18)F labeling of non-peptidic bivalent integrin αvβ3 antagonist for cancer imaging.
abstract: 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 αvβ3 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 αvβ3 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 αvβ3-specificity. In conclusion, the first (18)F labeled non-peptidic bivalent integrin αvβ3 targeting radiotracer, (18)F-bivalent-IA, was developed and proved to be a highly potent and specific PET radiopharmaceutical for noninvasive imaging of integrin αvβ3, which plays a critical role in tumor angiogenesis and metastasis.
authors.affiliation: Department of Translational Imaging, The Methodist Hospital Research Institute, Weill Medical College of Cornell University , 6670 Bertner Avenue, Houston, Texas 77030, United States.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D007553:Isotope Labeling; D051379:Mice; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: C519451:1,4,7-triazacyclononane-1,4-diacetate; D005462:Fluorine Radioisotopes; D006571:Heterocyclic Compounds; D039302:Integrin alphaVbeta3; D019275:Radiopharmaceuticals