title: Imaging herpes viral thymidine kinase-1 reporter gene expression with a new 18F-labeled probe: 2'-fluoro-2'-deoxy-5-[18F]fluoroethyl-1-beta-d-arabinofuranosyl uracil.
abstract: The preparation and radiolabeling of 2'-fluoro-2'-deoxy-1-beta-d-arabinofuranosyl-5-(2-fluoroethyl)-uracil (FFEAU) with 18F and its evaluation as a probe for imaging herpes simplex virus 1 thymidine kinase (HSV1-tk) gene expression are described. 2'-Fluoro-2'-deoxy-3',5'-di-O-benzoyl-1-beta-d-arabinofuranosyl-3-N-benzoyl-5-(2-[18F]fluoroethyl)-uracil 12 was prepared by nucleophilic substitution of the corresponding tosyl 8 or trifluoroethanesulfonyl 9 derivative with n-Bu4N[18F]F. Base hydrolysis was used to remove the benzoyl protecting groups, followed by HPLC purification, to afford [18F]FFEAU 13. The trifluoroethanesulfonyl substrate 9 appears to be the better labeling precursor. Carrier n-Bu4NF was added to the labeling reaction, which resulted in specific activities of 40-70 Ci/mmol (estimated). Radiochemical purity averaged 94+/-4%. Although [18F]FFEAU was obtained in low radiochemical yield with 9 and further optimization of the radiosynthesis will be required, sufficient product was available for a series of in vitro and in vivo studies. [18F]FFEAU was directly compared with [3H]TdR in a series of in vitro accumulation studies involving a HSV1-tk stably transduced cell line, RG2TK+ and a nontransduced, wild-type RG2 cells. The initial in vitro and in vivo imaging studies are promising; FFEAU has in vitro accumulation and sensitivity characteristics similar to that previously reported for FIAU, but greater selectivity than FIAU due to lower uptake and retention in nontransduced cells and tissues. The animal imaging experiment showed low levels of radioactivity in the lungs, with little or no radioactivity seen in the heart, liver, spleen and intestines.
authors.affiliation: Radiochemistry/Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Julius A
authors.initials: JA
authors.lastname: Balatoni
authors.forename: Michael
authors.initials: M
authors.lastname: Doubrovin
authors.forename: Ludmila
authors.initials: L
authors.lastname: Ageyeva
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetty
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Finn
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Blasberg
mesh_terms: D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods*; D017930:Genes, Reporter; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D013194:Staining and Labeling / Q000379:methods; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C508411:2'-fluoro-2'-deoxy-5-fluoroethyl-1-beta-D-arabinofuranosyl uracil; D019275:Radiopharmaceuticals; D014764:Viral Proteins; D001086:Arabinofuranosyluracil; C099241:thymidine kinase, Canid herpesvirus 1; D013937:Thymidine Kinase