2-(4-Bromo-2,5-dimethoxyphenyl)--(2-[C]methoxybenzyl)ethanamine

Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (1). It is involved in the 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, obsessive-compulsive disorder, and schizophrenia (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 three receptor subtypes within the G-protein–coupled 5-HT receptor family: 5-HT, 5-HT, and 5-HT. 5-HT receptors are abundantly present in the cerebral cortex, basal forebrain, hippocampus, amygdala, dorsal thalamus, hypothalamus, superior colliculus, substantia nigra, pedunculopontine nucleus, legmental area, and myelencephalon (5). 5-HT receptors are involved in mediation of normal and psychotic states, working memory, regulation of GABAergic and cholinergic neuronal cells, sleep, peripheral pain, and cardiovascular functions. 5-HT receptors are found mainly in several peripheral tissues, such as the stomach, intestine, pulmonary smooth muscle, and myocardium. In the brain, 5-HT receptors are found in discrete nuclei of the cerebellum, lateral septum, dorsal hypothalamus, dorsal raphe, and amygdala. 5-HT receptors are found in the choroid plexus, substantia nigra, globus pallidus, and ventromedial thalamus. 5-HT receptors are implicated in several psychiatric disorders, such as schizophrenia, depression, and obsessive-compulsive disorder. 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, such as [C]ketanserin (6), [F]spiperone (7), [C]methylspiperone ([C]NMSP), and [F]setoperone [PubMed], for positron emission tomography (8) imaging. However, none of these ligands has proven to be specific for 5-HT receptors because these compounds also bind to other receptors, such as dopamine receptors and the 5-HT receptor subtypes. Altanserin, a fluorobenzoyl derivative related to ketanserin, was reported to be a potent antagonist of 5-HT receptors with >100-fold selectivity over D receptors, 5-HT, 5-HT, and 5-HT (9, 10). This led to the development of 3-{2-[4-(4-[F]fluorobenzoyl)-1-piperidyl]ethyl}-2-sulfanyl-3-quinazolin-4-one ([F]altanserin) as a useful tool for 5-HT receptor PET imaging (11). 5-HT antagonists bind to the total pool of receptors, whereas 5-HT agonists bind only to the high-affinity functional state of the receptor but may be more important in disease states because the high affinity sites are the ones that transmit the intracellular signals. Furthermore, 2-(4-Iodo-2,5-dimethoxyphenyl)--(2-[C]methoxybenzyl)ethanamine ([C]CIMBI-5), a potent and selective 5-HT agonist, has been shown to have similar cortical binding potentials as compared with [F]altanserin in the pigs using the simplified reference tissue model (12). 2-(4-Bromo-2,5-dimethoxyphenyl)--(2-[C]methoxybenzyl)ethanamine ([C]CIMBI-36), a bromo analog of [C]CIMBI-5, has also been developed as a tool for studying 5-HT agonist binding in the brain (13).