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-β-D- arabinofuranosyluracil (FMAU) and its 5-substituted analogs involves stereospecific fluorination of the 1,3,5-tri-O-benzoyl-α-D-ribofuranose-2- sulfonate ester followed by bromination at the C₁-postion, and then coupling with pyrimidine-bis-trimethylsilyl ether. Several radiolabeled nucleoside analogs, including [¹⁸F]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 [¹⁸F]FMAU. The 2′-methylsulfonyl-3′,5′-O-tetrahydropyranyl-N ³-Boc-5-methyl-1-β-D-ribofuranosiluracil was synthesized in multiple steps. Radiofluorination of this precursor with K¹⁸F/ kryptofix produced 2′-deoxy-2′-[¹⁸F]fluoro-3′, 5′-O-tetrahydropyranyl-N³-Boc-5-methyl-1-β-D- arabinofuranosiluracil. Acid hydrolysis followed by high-performance liquid chromatography purification produced the desired [¹⁸F]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/μmol. Synthesis time was 95-100 min from the end of bombardment. This direct fluorination is a novel method for synthesis of [ ¹⁸F]FMAU, and the method should be suitable for production of other 5-substituted pyrimidine analogs, including [¹⁸F]FEAU, [ ¹⁸F]FIAU, [¹⁸F]FFAU, [¹⁸F]FCAU, and [ ¹⁸F]FBAU.