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

• Published in: Journal of labelled compounds & radiopharmaceuticals 2014-09, Vol.57 (11), p.637-644
• Main Authors: Meyer, Jan-Philip, Probst, Katrin C., Trist, Iuni M. L., McGuigan, Christopher, Westwell, Andrew D.
• Format: Article
• Language: English
• Subjects: computational chemistry; nucleosides; positron emission tomography; radiochemistry; radiopharmaceuticals
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.3233

18F‐FAC (1‐(2'‐deoxy‐2'‐[18F]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 18F‐FAC have relied on early introduction of the 18F radiolabel prior to attachment to protected cytosine base. Considering the 18F 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 18F‐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. 18F‐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. 18F‐FAC is an important 2′‐fluoro‐nucleoside‐based positron emission tomography radiotracer that has been used for in vivo prediction of response to the widely used cancer chemotherapy drug gemcitabine. Previously reported radiosynthetic routes to 18F‐FAC have relied on early stage introduction of the 18F radiolabel (half‐life = 100 min). We present the first late‐stage radiosynthesis of 18F‐FAC from a rationally designed precursor with a good reactivity‐to‐stability ratio at elevated temperatures.