3-[2-[4-(4-[18F]Fluorobenzoyl)-1-piperidyl]ethyl]-2-sulfanyl-3 H-quinazolin-4-one

Excerpt

Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiologic roles as a neurotransmitter in the central nervous system (1). It 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, obsessive-compulsive disorder, and schizophrenia (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT₁ to 5-HT₇), many of which include several subtypes (4). There are three receptor subtypes within the G protein-coupled 5-HT₂ receptor family: 5-HT_2A, 5-HT_2B, and 5-HT_2C.

5-HT_2A 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_2A 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_2B receptors are found mainly in several peripheral tissues, such as the stomach, intestine, and pulmonary smooth muscle, and in the myocardium. In the brain, 5-HT_2B receptors are found in discrete nuclei of the cerebellum, lateral septum, dorsal hypothalamus, dorsal raphe, and amygdala. 5-HT_2C receptors are found in the choroid plexus, substantia nigra, globus pallidus, and ventromedial thalamus. 5-HT_2A 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 pharmacologic role of 5-HT_2A receptors.

There have been several studies to develop specific 5-HT_2A radioligands, such as [¹¹C]ketanserin (6), [¹⁸F]spiperone (7), [¹¹C]methylspiperone ([¹¹C]NMSP), and [¹⁸F]setoperone [PubMed], for positron emission tomography (PET) imaging. However, none has proven specific for 5-HT_2A receptors because these compounds also bind to other receptors, such as dopamine receptors and 5-HT₁ receptor subtypes. Altanserin, a fluorobenzoyl derivative related to ketanserin, was reported to be a potent inhibitor of 5-HT_2A receptors with >100-fold selectivity over D_2/3 receptors, 5-HT_1A, 5-HT₆, and 5-HT₇ (8, 9). This led to the development of 3-[2-[4-(4-[¹⁸F]fluorobenzoyl)-1-piperidyl]ethyl]-2-sulfanyl-3H-quinazolin-4-one ([¹⁸F]altanserin) as a useful tool for 5-HT_2A receptor PET imaging in vivo (10).