3-Chloro-4-[F]fluorophenyl-(4-fluoro-4-[[((5-methyl-4-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone (F13714)

5-Hydroxytryptamine (5-HT), commonly known as serotonin, has diverse physiological roles as a neurotransmitter in the central nervous system (1). 5-HT is involved in regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, schizophrenia, and obsessive-compulsive disorder (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT to 5-HT), many of which include several subtypes (4). There are five receptor subtypes within the G-protein–coupled 5-HT receptor family: 5-HT, 5-HT, 5-HT, 5-HT, and 5-HT. 5-HT receptors are abundantly present in the hippocampus, entorhinal cortex, frontal cortex, raphe nucleus, and septum; the lowest densities are observed in the basal ganglia, substantia nigra, and cerebellum (5). Some thalamic and hypothalamic nuclei have intermediate densities. 5-HT receptors are involved in the mediation of emotion and the function of the hypothalamus. 5-HT receptors are implicated in anxiety, depression, hallucinogenic behavior, motion sickness, and eating disorders (6). Thus, there is a need for selective ligands to investigate the pharmacological role of 5-HT receptors. There have been several studies to develop specific 5-HT radioligands [PubMed] for positron emission tomography (PET) imaging, such as [-C]WAY 100635, [F]FPWAY, and [F]MPPF. However, none of these antagonists distinguishes between the high- and low-affinity states of the 5-HT receptors. The high-affinity state of the receptor is coupled to G-proteins, which mediate cell functions by providing intracellular signals. 2-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2,4)dione (MMP) was reported to be a potent agonist of 5-HT receptors ( = 0.15 nM) (7). This led to the development of [O--C]MMP ([C]MMP, also known as [C]CUMI-101) as a useful tool for PET imaging of the 5-HT receptor (8-10). However, [C]CUMI-101 was shown to be a partial 5-HT agonist and therefore was less efficient in mediating cell function (11, 12). 3-Chloro-4-[F]fluorophenyl-(4-fluoro-4-[[((5-methyl-4-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl)methanone ([F]F13714) was evaluated as a PET probe for the 5-HT receptor because unlabeled F13714 was found to be a selective 5-HT agonist with subnanomolar affinity for the 5-HT receptor (13).