The serotonin 2C receptor subtype (5-HT) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT PET radiotracers such as [C]N-methylated arylazepine (1), [C]WAY-163909 (2), and [F]fluorophenylcyclopropane (3) have been developed, but they may not be suitable for in vivo 5-HT imaging study due to their modest specific binding. Herein, the synthesis and in vivo evaluation of 4-(3-[F]fluorophenethoxy)pyrimidine [F]4 as a potential PET radiotracer for the 5-HT receptor is described. [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 [F]4 with or without lorcaserin, a U.S. Food and Drug Administration approved selective 5-HT agonist, demonstrated that [F]4 exhibits a high level of specific binding to 5-HT receptors in the rat brain.

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Metabotropic glutamate receptor 1 (mGluR1) is considered as an attractive drug target for neuropathic pain treatments. The hierarchical virtual screening approach for identifying novel scaffolds of mGluR1 allosteric modulators was performed using a homology model built with the dopamine D3 crystal structure as template. The mGluR1 mutagenesis data, conserved amino acid sequences across class A and class C GPCRs, and previously reported multiple sequence alignments of class C GPCRs to the rhodopsin template, were employed for the sequence alignment to overcome difficulties of model generation with low sequence identity of mGluR1 and dopamine D3. The structures refined by molecular dynamics simulations were employed for docking of Asinex commercial libraries after hierarchical virtual screening with pharmacophore and naïve Bayesian models. Five of 35 compounds experimentally evaluated using a calcium mobilization assay exhibited micromolar activities (IC50) with chemotype novelty that demonstrated the validity of our methods. A hierarchical structure and ligand-based virtual screening approach with homology model of class C GPCR based on dopamine D3 class A GPCR structure was successfully performed and applied to discover novel negative mGluR1 allosteric modulators.