title: Novel synthesis and preclinical evaluation of folic acid derivatives labeled with (18)F-[FDG] for PET imaging of folate receptor-positive tumors.
abstract: There is a need to develop more potent radiofluorinated folic acid conjugates for a better visualization of folate receptors that overexpress on many human cancers. Due to the clinical importance of [(18)F]-fluoro-2-deoxy-d-glucose ([(18)F]-FDG) and its availability in almost every positron-emission tomography center, new radiofluorinated [(18)F]-FDG-folate and methotrexate conjugates ([(18)F]-5 and [(18)F]-8) were synthesized using [(18)F]-FDG as a prosthetic group. In a convenient and simple one-step radiosynthesis, [(18)F]-5 and [(18)F]-8 conjugates were prepared in high radiochemical yields (>80%) with total synthesis time of almost 20 min, and radiochemical purities were found to be greater than 98% without high-performance liquid chromatography purification, which make these approaches amenable for automation. In vitro tests on KB cell line showed that a significant amount of the radioconjugates were associated with the cell fractions. In vivo characterization in normal Balb/c mice revealed rapid blood clearance of these radioconjugates with excretion predominantly by the urinary and hepatobiliary systems for [(18)F]-5 and [(18)F]-8 conjugates, respectively. Biodistribution studies in nude mice-bearing human KB cell line xenografts demonstrated significant tumor uptake and favorable kinetics profile for [(18)F]-5 over the other conjugate. The uptake in the tumors was blocked by the excess coinjection of cold folic acid, suggesting the receptor-mediated process. These results demonstrate that [(18)F]-5 may be useful as a molecular probe for detecting and staging of folate receptor-positive cancers, such as ovarian cancer and their metastasis, as well as monitoring tumor response to the treatment.
authors.affiliation: Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. jammaz@kfshrc.edu.sa
authors.forename: I
authors.initials: I
authors.lastname: Al Jammaz
authors.forename: B
authors.initials: B
authors.lastname: Al-Otaibi
authors.forename: S
authors.initials: S
authors.lastname: Amer
authors.forename: N
authors.initials: N
authors.lastname: Al-Hokbany
authors.forename: S
authors.initials: S
authors.lastname: Okarvi
mesh_terms: D000818:Animals; D001692:Biological Transport; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005260:Female; D019788:Fluorodeoxyglucose F18; D005492:Folic Acid / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D058972:Folic Acid Transporters / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D007624:KB Cells; D008727:Methotrexate / Q000737:chemistry; D051379:Mice; D009062:Mouth Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D049268:Positron-Emission Tomography / Q000379:methods*
chemical_list: D058972:Folic Acid Transporters; D019788:Fluorodeoxyglucose F18; D005492:Folic Acid; D008727:Methotrexate