title: Synthesis and evaluation of a 18F-labeled 4-ipomeanol as an imaging agent for CYP4B1 gene prodrug activation therapy.
abstract: We report the development of a (18)F-labeled 4-ipomeanol (4-IM), which is metabolized by the CYP4B1 enzyme, to image tumors and monitor enzyme-activating anticancer prodrugs. The fluorine-substituted derivative, 1-(3-furyl)-4-hydroxy-5-fluoro-1-pentanone (F-4-IM, 1), was synthesized from 3-furaldehyde. [(18)F]F-4-IM ([(18)F]1) was prepared in 20%-35% radiochemical yield by a fluorine-18 displacement reaction, followed by reduction and deprotection of the ketal group, and was shown to be stable (>96% at 2 hours) in human serum at 37°C. The biodistribution of [(18)F]F-4-IM in normal rats was high in the lung, where CYP4B1 gene is preferentially expressed. We transduced C6-glioma cells with a retrovirus-expressing CYP4B1 (C6-CYP4B1). Evaluation of CYP4B1 expression was confirmed by reverse transcription polymerase chain reaction and MTT assay. Cell assays were carried out using C6 and C6-CYP4B, and the uptake of [(18)F]F-4-IM in these cells was compared with that in parental controls. The uptake ratio of [(18)F]F-4-IM was 2.8-fold higher in C6-CYP4B1 compared with that in parental cells at 1 hour, whereas [(3)H]4-IM was taken up at similar rates in both cell lines after 6 hours. These results suggest that [(18)F]F-4-IM could be a promising PET imaging agent with potential to be used for imaging of CYP4B1-transfected tumor cells, as well as for monitoring CYP4B1 enzyme/prodrug interactions.
authors.affiliation: 1 Department of Nuclear Medicine, Seoul National University Bundang Hospital , Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byung Seok
authors.initials: BS
authors.lastname: Moon
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Jang
authors.forename: Sung Joo
authors.initials: SJ
authors.lastname: Kim
authors.forename: Tae Sup
authors.initials: TS
authors.lastname: Lee
authors.forename: Dae Yoon
authors.initials: DY
authors.lastname: Chi
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Lee
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Sang Eun
authors.initials: SE
authors.lastname: Kim
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004355:Drug Stability; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D011355:Prodrugs / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D013729:Terpenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D005462:Fluorine Radioisotopes; D011355:Prodrugs; D019275:Radiopharmaceuticals; D013729:Terpenes; D001189:Aryl Hydrocarbon Hydroxylases; C095029:cytochrome P-450 CYP4B1; C001470:4-ipomeanol