A novel method for stereospecific fluorination at the 2′-arabino-position of pyrimidine nucleoside: synthesis of [18F]-FMAU

Direct fluorination of a pyrimidine nucleoside at the 2'-arabino-position has been deemed to be extremely difficult, if not impossible. The conventional synthesis of 2'-deoxy-2'-fluoro-5-methy-1-beta-D-arabinofuranosyluracil (FMAU) and its 5-substituted analogs involves stereospecific fluorination of the 1,3,5-tri-O-benzoyl-alpha-D-ribofuranose-2-sulfonate ester followed by bromination at the C-1-postion, and then coupling with pyrimidine-bis-trimethylsilyl ether. Several radiolabeled nucleoside analogs, including [F-18]FMAU, and other 5-substituted analogs, were developed according to this methodology. However, routine production of these compounds using this multi-step process is inconvenient and limits their clinical application. We developed a novel precursor and method for direct fluorination of preformed nucleoside analogs at the 2'-arabino position, exemplified via radiosynthesis of [F-18]FMAU. The 2'-methylsulfony1-3',5'-O-tetrahydropyranyl-N-3-Boc-5-methyl-1-beta-D-ribofuranosiluracil was synthesized in multiple steps. Radiofluorination of this precursor with (KF)-F-18/kryptofix produced 2'-deoxy-2'[F-18]fluoro-3',5'-O-tetrahydropyranyl-N-3-Boc-5-methyl-1-beta-D-arabinofuranosiluracil. Acid hydrolysis followed by high-performance liquid chromatography purification produced the desired [F-18]FMAU. The average radiochemical yield was 2.0% (decay corrected, n=6), from the end of bombardment. Radiochemical purity was >99%, and specific activity was >1800 mCi/mu mol. Synthesis time was 95-100 min from the end of bombardment. This direct fluorination is a novel method for synthesis of [F-18]FMAU, and the method should be suitable for production of other 5-substituted pyrimidine analogs, including [F-18]FEAU, [F-18]FIAU, [F-18]FFAU, [F-18]FCAU, and [F-18]FBAU.