A Potential PET Radiotracer for the 5-HT_2C Receptor: Synthesis and in Vivo Evaluation of 4-(3-[¹⁸F]fluorophenethoxy)pyrimidine

The serotonin 2C receptor subtype (5-HT_2C) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT_2C receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT_2C receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT_2C 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-HT_2C imaging study due to their modest specific binding. Herein, the synthesis and in vivo evaluation of 4-(3-[¹⁸F]fluorophenethoxy)pyrimidine [¹⁸F]4 as a potential PET radiotracer for the 5-HT_2C receptor is described. [¹⁸F]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 [¹⁸F]4 with or without lorcaserin, a U.S. Food and Drug Administration approved selective 5-HT_2C agonist, demonstrated that [¹⁸F]4 exhibits a high level of specific binding to 5-HT_2C receptors in the rat brain.