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 18FFMAU, 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 18FFMAU. 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′‐18Ffluoro‐3′,5′‐O‐tetrahydropyranyl‐N3‐Boc‐5‐methyl‐1‐β‐D‐arabinofuranosiluracil. Acid hydrolysis followed by high‐performance liquid chromatography purification produced the desired 18FFMAU. 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 18FFMAU, and the method should be suitable for production of other 5‐substituted pyrimidine analogs, including 18FFEAU, 18FFIAU, 18FFFAU, 18FFCAU, and 18FFBAU. Copyright © 2010 John Wiley & Sons, Ltd. Direct fluorination of a pyrimidine nucleoside at the 2′‐arabino‐position has been extremely difficult. Radiosynthesis of 18FFMAU involves multi‐step process, which is inconvenient. We have developed a novel method for direct fluorination at the 2′‐arabino‐position of the nucleoside for radiosynthesis of 18FFMAU. A precursor compound, 2′‐methylsulfonyl‐3′,5′‐O‐tetrahydropyranyl‐N3‐Boc‐5‐methyl‐1‐β‐D‐ribofuranosiluracil 7, was fluorinated with K18F/kryptofix. The crude product was hydrolyzed and purified by HPLC to obtain 18FFMAU 8. This method should be suitable for radiosynthesis of other analogs such as 18FFEAU, 18FFIAU, etc. for PET. Copyright © 2010 John Wiley & Sons, Ltd.