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

Abstract

Direct fluorination of a pyrimidine nucleoside at the 2 0 -arabino-position has been deemed to be extremely difficult, if not impossible. The conventional synthesis of 2 0 -deoxy-2 0 -fluoro-5-methy-1-b-D-arabinofuranosyluracil (FMAU) and its 5-substituted analogs involves stereospecific fluorination of the 1,3,5-tri-O-benzoyl-a-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 [18 F]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 0 -arabino position, exemplified via radiosynthesis of -Boc-5-methyl-1-b-D-arabinofuranosiluracil. Acid hydrolysis followed by high-performance liquid chromatography purification produced the desired [18 F]FMAU. The average radiochemical yield was 2.0% (decay corrected, n = 6), from the end of bombardment. Radiochemical purity was 499%, and specific activity was 41800 mCi/mmol. Synthesis time was 95-100 min from the end of bombardment. This direct fluorination is a novel method for synthesis of

An improved strategy for the synthesis of [18F]-labeled arabinofuranosyl nucleosides

“…Further, the fluorine exchange from TMSOTf or one of the byproducts may result in lower specific activity. Our [ 18 F]-FMAU and [ 18 F]-FEAU (Table 4) synthesis afforded 2–3 fold lower specific activities than the highest specific activity reported in the literature (Table 4) [15, 18, 33, 36]. We obtained the highest specific activity with this method for [ 18 F]-FIAU.…”

“…Although direct fluorination of the nucleoside at the 2′-position of the sugar is the simplest way to synthesize these 18 F-labeled pyrimidine derivatives, this approach cannot be applied to routine clinical production, because the reported overall yields are less than 1%, quite low for routine clinical use [18]. …”

A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[18F]fluoro‐β‐d‐arabinofuranosyl)cytosine (18F‐FAC)

“…Late-stage 18 F-introduction at the 2'-arabino position of an intact nucleoside towards nucleoside-based radiotracers was previously considered as difficult. [12] However, Alauddin and co-workers recently developed a novel radiosynthesis of the uridine analogue 18 F-FMAU based on a late-stage 18 F-introduction approach in order to increase possibilities for making nucleoside based PET tracer suitable for clinical applications. [10,12] The key towards a stable precursor that would be less likely to undergo anhydro side product formation (e.g.…”

“…[12] However, Alauddin and co-workers recently developed a novel radiosynthesis of the uridine analogue 18 F-FMAU based on a late-stage 18 F-introduction approach in order to increase possibilities for making nucleoside based PET tracer suitable for clinical applications. [10,12] The key towards a stable precursor that would be less likely to undergo anhydro side product formation (e.g. Scheme 1) due to neighbouring group participation was the introduction of a good electron withdrawing N-protecting group(s).…”

An investigation on stereospecific fluorination at the 2′-arabino-position of a pyrimidine nucleoside: radiosynthesis of 2′-deoxy-2′-[18F]fluoro-5-methyl-1-β-d-arabinofuranosyluracil

“…Most recently, we reported a synthesis of 2′-arabino-fluoro-derivative ([ 18 F]FMAU) for the 4′-oxo-nucleoside by stereospecific fluorination. 34 In this method the N 3 -proton was substituted with t -butyloxycarbonyl (Boc) and a precursor compound, 2′-methylsulfonyl-3′,5′-O-tetrahydropyranyl-N 3 -Boc-5-methyl-1-β-D-ribofuranosil-uracil, was synthesized in multiple steps. Radiofluorination of this precursor was performed with K[ 18 F]/kryptofix 2.2.2. to produce 2′-deoxy-2′-[ 18 F]fluoro-3′,5′-O-tetrahydropyranyl-N 3 -Boc-5-methyl-1-β-D-arabinofuranosyluracil.…”