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

¹ Department of Chemistry and Applied Biosciences of ETH, Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Zurich, Switzerland; ² Department of Nuclear Medicine, Cantonal Hospital, Aarau, Switzerland; and ³ Merck Eprova AG, Schaffhausen, Switzerland

Correspondence: For correspondence or reprints contact: Simon M. Ametamey, PhD, Center for Radiopharmaceutical Science of ETH, PSI, and USZ, ETH Hönggerberg Wolfgang Pauli Strasse 10, CH-8093 Zurich, Switzerland. E-mail: simon.ametamey{at}pharma.ethz.ch

Folic acid was linked regioselectively through its - and -carboxyl groups to 4-fluorobenzylamine (FBA), and the - and -FBA-folate regioisomers were evaluated for their ability to bind to folate receptor–positive cells. The ¹⁸F-labeled /-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor–positive tumor cells. Methods: ¹⁸F-/-FBA-folate was prepared in a 4-step reaction sequence starting from folic acid. The relative binding affinities of the - and -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 /-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/µmol. The in vitro binding affinities of the - and -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%—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.

Key Words: folate receptor • ¹⁸F labeling • PET • tumor imaging

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