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

Abstract

AbstractDirect 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‐N3‐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. Copyright © 2010 John Wiley & Sons, Ltd.