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

Abstract

Direct fluorination at the 2′-arabino-position of a pyrimidine nucleoside has been a long-standing challenge, yet we recently reported such a stereospecific fluorination for the first time in the synthesis of [18F]FMAU, albeit in low yields. Herein we report the results of an investigation on stereospecific fluorination on a variety of precursors for synthesis of [18F]FMAU. Several precursors were synthesized in multiple steps and fluorination was performed at the 2′-arabino position using K[18F]/kryptofix 2.2.2. All precursors produced [18F]FMAU in low yields.

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

“…The choice of the leaving group as well as the protecting group is based on a previous study [10] that found that 3'/5'-THP-protection of uridine derivatives gave the best radiochemical yields and a 2'-mesyl group an appropriate balance between stability and leaving group abilities. Furthermore, our pilot studies showed that the appropriate tosyl-and nosyl-containing counterparts already decomposed during purification.…”

“…[9] However, this synthetic approach limits reliable and reproducible production on commercially available synthesis modules for human application. [10] For instance, multiple steps after 18 F introduction with an additional purification step due to the formation of the D-and Lisomers, as well as the use of toxic substances such as hydrogen bromide, make the translation to automated synthesizers difficult. These challenges go hand in hand with reproducibility issues when it comes to Quality Control (QC) in clinical practice according to the British/European/American Pharmacopeia (BPh/Ph.…”

“…[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).…”

“…Calculated electron density Ω of selected cytidine (4)(5)(6)(7)(8) and uridine derivatives (9)(10)(11) [a] Quantum chemically calculated net charge at the 2-carbonyl oxygen. …”

Radiochemical synthesis of 2′‐[18F]‐labelled and 3′‐[18F]‐labelled nucleosides for positron emission tomography imaging

“…Bromination and subsequent condensation of 12 with the appropriate 2,4‐ bis‐O –(trimethylsilyl)pyrimidine followed by deprotection produced a mixture of the desired β ‐anomers and α ‐anomers 3 and 3b in a ratio of 3/1 to 8/1 depending on the reaction solvent, obtaining a radiochemical yield up to 45% of the correct stereoisomer . Even though the nucleoside radiotracers were obtained in good radiochemical yields and high purities, this synthetic approach reveals issues that inhibit these PET probes from being produced on commercially available synthesis modules for routine production and human application . For instance, multiple steps after [ 18 F]‐introduction with an additional purification step due to the formation of the d ‐isomers and l ‐isomers, as well as the use of toxic substances such as HBr, make the translation to automated synthesisers difficult.…”