title: Synthesis and preclinical evaluation of a folic acid derivative labeled with 18F for PET imaging of folate receptor-positive tumors.
abstract: Folic acid was linked regioselectively through its alpha- and gamma-carboxyl groups to 4-fluorobenzylamine (FBA), and the alpha- and gamma-FBA-folate regioisomers were evaluated for their ability to bind to folate receptor-positive cells. The 18F-labeled alpha/gamma-FBA-folate counterpart was examined for in vivo tumor targeting efficiency in nude mice bearing folate receptor-positive tumor cells.
  
  
  METHODS
  18F-alpha/gamma-FBA-folate was prepared in a 4-step reaction sequence starting from folic acid. The relative binding affinities of the alpha- and gamma-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 alpha/gamma-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/micromol. The in vitro binding affinities of the alpha- and gamma-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).
  
  
  CONCLUSIONS
  This new 18F-labeled folic acid derivative is a promising tool for PET imaging of folate receptor-positive tumors.
authors.affiliation: Department of Chemistry and Applied Biosciences of ETH, Center for Radiopharmaceutical Science of ETH, PSI, and USZ, Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bettio
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Cristina
authors.initials: C
authors.lastname: Müller
authors.forename: Matthias
authors.initials: M
authors.lastname: Brühlmeier
authors.forename: Ursina
authors.initials: U
authors.lastname: Müller
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.forename: Viola
authors.initials: V
authors.lastname: Groehn
authors.forename: August P
authors.initials: AP
authors.lastname: Schubiger
authors.forename: Simon M
authors.initials: SM
authors.lastname: Ametamey
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis*
chemical_list: D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D019275:Radiopharmaceuticals; D011956:Receptors, Cell Surface; D019788:Fluorodeoxyglucose F18; D005492:Folic Acid