A Potential PET Radiotracer for the 5‑HT2C Receptor: Synthesis and in Vivo Evaluation of 4‑(3‑[18F]fluorophenethoxy)pyrimidine

The serotonin 2C receptor subtype (5-HT2C) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT2C receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT2C receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT2C PET radiotracers such as [11C]N-methylated arylazepine (1), [11C]­WAY-163909 (2), and [18F]­fluorophenylcyclopropane (3) have been developed, but they may not be suitable for in vivo 5-HT2C imaging study due to their modest specific binding. Herein, the synthesis and in vivo evaluation of 4-(3-[18F]­fluorophenethoxy)­pyrimidine [ 18 F]­4 as a potential PET radiotracer for the 5-HT2C receptor is described. [ 18 F]­4 was synthesized by nucleophilic aromatic substitution of diaryliodonium precursor 17a with a 7.8 ± 2.7% (n = 6, decay corrected) radiochemical yield and over 99% radiochemical purity, showing an 89 ± 14 GBq/μmol specific radioactivity. The in vivo PET imaging studies of [ 18 F]­4 with or without lorcaserin, a U.S. Food and Drug Administration approved selective 5-HT2C agonist, demonstrated that [ 18 F]­4 exhibits a high level of specific binding to 5-HT2C receptors in the rat brain.