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

Abstract

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 gamma-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 [C-11]N-methylated arylazepine (1), [C-11]WAY-163909 (2), and [F-18]-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-[F-18]fluorophenethoxy)pyrimidine [F-18]4 as potential PET radiotracer for the 5-HT2C receptor is evaluation of 4-(3- a described. [F-18]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/mu mol specific radioactivity. The in vivo PET imaging studies of [F-18]4 with or without lorcaserin, a U.S. Food and Drug Administration approved selective 5-HT2C agonist, demonstrated that [F-18]4 exhibits a high level of specific binding to 5-HT2C receptors in the rat brain.