title: A novel radiochemical approach to 1-(2'-deoxy-2'-[(18) F]fluoro-β-d-arabinofuranosyl)cytosine ((18) F-FAC).
abstract: (18) F-FAC (1-(2'-deoxy-2'-[(18) F]fluoro-β-D-arabinofuranosyl)-cytosine) is an important 2'-fluoro-nucleoside-based positron emission tomography (PET) tracer that has been used for in vivo prediction of response to the widely used cancer chemotherapy drug gemcitabine. Previously reported synthetic routes to (18) F-FAC have relied on early introduction of the (18) F radiolabel prior to attachment to protected cytosine base. Considering the (18) F radiochemical half-life (110 min) and the technical challenges of multi-step syntheses on PET radiochemistry modular systems, late-stage radiofluorination is preferred for reproducible and reliable radiosynthesis with in vivo applications. Herein, we report the first late-stage radiosynthesis of (18) F-FAC. Cytidine derivatives with leaving groups at the 2'-position are particularly prone to undergo anhydro side-product formation upon heating because of their electron density at the 2-carbonyl pyrimidone oxygen. Our rationally developed fluorination precursor showed an improved reactivity-to-stability ratio at elevated temperatures. (18) F-FAC was obtained in radiochemical yields of 4.3-5.5% (n = 8, decay-corrected from end of bombardment), with purities ≥98% and specific activities ≥63 GBq/µmol. The synthesis time was 168 min.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, Wales, UK; Wales Research & Diagnostic PET Imaging Centre (PETIC), Institute for Translation, Innovation, Methodology & Engagement (TIME), School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, Wales, UK.
authors.forename: Jan-Philip
authors.initials: JP
authors.lastname: Meyer
authors.forename: Katrin C
authors.initials: KC
authors.lastname: Probst
authors.forename: Iuni M L
authors.initials: IM
authors.lastname: Trist
authors.forename: Christopher
authors.initials: C
authors.lastname: McGuigan
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westwell
mesh_terms: D003561:Cytarabine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*
chemical_list: C571030:1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine; D019275:Radiopharmaceuticals; D003561:Cytarabine
keywords: computational chemistry; nucleosides; positron emission tomography; radiochemistry; radiopharmaceuticals