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Semiautomated radiosynthesis and biological evaluation of [18F]FEAU: a novel PET imaging agent for HSV1-tk/sr39tk reporter gene expression. 2008

Frederick T Chin, and Mohammed Namavari, and Jelena Levi, and Murugesan Subbarayan, and Pritha Ray, and Xiaoyuan Chen, and Sanjiv S Gambhir
Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305-5484, USA.

2'-deoxy-2'-[(18)F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil ([(18)F]FEAU) is a promising radiolabeled nucleoside designed to monitor Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk) reporter gene expression with positron emission tomography (PET). However, the challenging radiosynthesis creates problems for being able to provide [(18)F]FEAU routinely. We have developed a routine method using a commercial GE TRACERlab FX-FN radiosynthesis module with customized equipment to provide [(18)F]FEAU. All radiochemical yields are decay corrected to end-of-bombardment and reported as means +/- SD. Radiofluorination (33 +/- 8%; n = 4), bromination (85 +/- 8%; n = 4), coupling reaction (83 +/- 6%; n = 4), base hydrolysis steps, and subsequent high-performance liquid chromatography purification afforded purified [(18)F]FEAU beta-anomer in 5 +/- 1% overall yield (n = 3 runs) after approximately 5.5 h and a beta/alpha-anomer ratio of 7.4. Radiochemical/chemical purities and specific activity exceeded 99% and 1.3 Ci/micromol (48 GBq/micromol), respectively. In cell culture, [(18)F]FEAU showed significantly (P < 0.05) higher accumulation in C6 cells expressing HSV1-tk/sr39tk as compared to wild-type C6 cells. Furthermore, [(18)F]FEAU showed slightly higher accumulation than 9-[4-[(18)F]fluoro-3-(hydroxymethyl)butylguanine ([(18)F]FHBG) in cells expressing HSV1-tk (P < 0.05), whereas [(18)F]FHBG showed significantly higher (P < 0.05) accumulation than [(18)F]FEAU in HSV1-sr39tk-expressing cells. micro-PET imaging of mice carrying tumor xenografts of C6 cells stably expressing HSV1-tk or HSV1-sr39tk are consistent with the cell uptake results. The [(18)F]FEAU mouse images also showed very low gastrointestinal signal with predominant renal clearance as compared to [(18)F]FHBG. The routine radiosynthesis of [(18)F]FEAU was successfully semiautomated using a commercial module along with customized equipment to provide the beta-anomer in modest yields. Although further studies are needed, early results also suggest [(18)F]FEAU is a promising PET radiotracer for monitoring HSV1-tk reporter gene expression.

UI MeSH Term Description Entries
D008819 Mice, Nude Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses. Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D009368 Neoplasm Transplantation Experimental transplantation of neoplasms in laboratory animals for research purposes. Transplantation, Neoplasm,Neoplasm Transplantations,Transplantations, Neoplasm
D002851 Chromatography, High Pressure Liquid Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed. Chromatography, High Performance Liquid,Chromatography, High Speed Liquid,Chromatography, Liquid, High Pressure,HPLC,High Performance Liquid Chromatography,High-Performance Liquid Chromatography,UPLC,Ultra Performance Liquid Chromatography,Chromatography, High-Performance Liquid,High-Performance Liquid Chromatographies,Liquid Chromatography, High-Performance
D005462 Fluorine Radioisotopes Unstable isotopes of fluorine that decay or disintegrate emitting radiation. F atoms with atomic weights 17, 18, and 20-22 are radioactive fluorine isotopes. Radioisotopes, Fluorine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001086 Arabinofuranosyluracil A pyrimidine nucleoside formed in the body by the deamination of CYTARABINE. Ara-U,Arabinosyluracil,Arauridine,Sponguridine,Uracil Arabinofuranoside,Uracil Arabinoside,1-beta-D-Arabinofuranosyl Uracil,NSC 68928,1 beta D Arabinofuranosyl Uracil,Ara U,Arabinofuranoside, Uracil,Arabinoside, Uracil,Uracil, 1-beta-D-Arabinofuranosyl
D013056 Spectrophotometry, Ultraviolet Determination of the spectra of ultraviolet absorption by specific molecules in gases or liquids, for example Cl2, SO2, NO2, CS2, ozone, mercury vapor, and various unsaturated compounds. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) Ultraviolet Spectrophotometry
D013937 Thymidine Kinase An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 2.7.1.21. Deoxythymidine Kinase,Deoxypyrimidine Kinase,Kinase, Deoxypyrimidine,Kinase, Deoxythymidine,Kinase, Thymidine
D014162 Transfection The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES. Transfections
D015870 Gene Expression The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION. Expression, Gene,Expressions, Gene,Gene Expressions

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