Synthesis and Preclinical Evaluation of a Folic Acid Derivative Labeled with 18F for PET Imaging of Folate Receptor-Positive Tumors

摘要

id="p-1">Folic acid was linked regioselectively through its ?±- and ?3-carboxyl groups to 4-fluorobenzylamine (FBA), and the ?±- and ?3-FBA-folate regioisomers were evaluated for their ability to bind to folate receptor-positive cells. The 18F-labeled ?±/?3-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor-positive tumor cells. >Methods: 18F-?±/?3-FBA-folate was prepared in a 4-step reaction sequence starting from folic acid. The relative binding affinities of the ?±- and ?3-FBA-folates to the folate receptor with respect to parent folic acid were determined in cultured KB-31 cells (nasopharyngeal epidermal carcinoma cell line) overexpressing the folate receptor using 3H-folic acid. Tumor accumulation of the 18F-labeled ?±/?3-FBA-folate and 18F-FDG was analyzed in vivo by high-resolution PET. Biodistribution and PET studies were performed under baseline and blockage conditions. >Results: The radiochemical yield of the coupling step ranged from 15% to 44%, and the maximum specific radioactivity was 24 GBq/??mol. The in vitro binding affinities of the ?±- and ?3-isomers and folic acid were 71, 62, and 41 nmol/L, respectively. PET revealed heterogeneous uptake of the radioligand, with the highest activity concentrations found in the tumor rim. In contrast, 18F-FDG uptake in a nude mouse bearing KB-31 folate receptor-positive tumors was negligible. Radioligand uptake in tumors at 125 min after injection amounted to 6.56% of the injected dose per gram of tissue (%ID/g) in control animals, whereas radioactivity accumulation in the tumors of folic acid-treated animals was significantly reduced by more than 80%a€”to 1.07 %ID/g (P = 0.001). >Conclusion: This new 18F-labeled folic acid derivative is a promising tool for PET imaging of folate receptor-positive tumors.