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

Abstract

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-[ 18F]fluoro-N 4-(pentyloxycarbonyl)cytidine ([ 18F]Xeloda; [ 18F] 1) was prepared by nucleophilic substitution of the nitro-precursor with K 18F/Kryptofix 2.2.2 followed by a quick deprotection reaction and purification with the HPLC method in 20–30% radiochemical yields.