Synthesis of [18F]Xeloda as a novel potential PET radiotracer for imaging enzymes in cancers

Xeloda (Capecitabine), a prodrug of antitumor agent 5-fluorouracil, is the first and only oral fluoropyrimidine to be approved for use as second-line therapy in metastatic breast cancer, colorectal cancer, and other solid malignancies. Fluorine-18 labeled Xeloda may serve as a novel radiotracer for positron emission tomography (PET) to image enzymes such as thymidine phosphorylase and uridine phosphorylase in cancers. The precursor 2',3'-di-O-acetyl-5'-deoxy-5-nitro-N-4-(pentyloxycarbonyl)cytidine (11) was synthesized from D-ribose and cytosine in 8 steps with approximately 18% overall chemical yield. The reference standard 5'-deoxy-5-fluoro-N-4-(pentyloxycarbonyl)cytidine (Xeloda; 1) was synthesized from D-ribose and 5-fluorocytosine in eight steps with approximately 28% overall chemical yield. The target radiotracer 5'-deoxy-5-[F-18]fluoro-N-4- (pentyloxycarbonyl)cytidine ([F-18]Xeloda; [F-18]1) was prepared by nucleophilic substitution of the nitro-precursor with (KF)-F-18/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with the HPLC method in 20-30% radiochemical yields. (C) 2004 Elsevier Inc. All rights reserved.