[F]3-(1-Imidazol-4-yl)propyl-4-fluorobenzyl ether

Histamine is a major neurotransmitter that plays important physiological roles (1, 2). There are four histamine receptor subtypes (H to H) (3). Histamine H receptors (HRs) are presynaptic autoreceptors that negatively regulate the release of histamine and other neurotransmitters such as norepinephrine, GABA, dopamine, and acetylcholine in the central nervous system (CNS) (4). Consistent with the widespread projection of histaminergic neurons from the lateral hypothalamus, HRs are widely distributed in the CNS with high densities in the basal ganglia and are believed to play a variety of physiological roles, including regulation of feeding, arousal, cognition, pain, and endocrine systems (5-7). The HRs are also found in a wide variety of peripheral tissues (4). The HRs are GTP-binding-protein (G-protein)–coupled receptors that decrease Ca influx into the cell and inhibit adenylyl cyclase. Positron emission tomography (PET) and single-photon emission tomography of radioligands targeting histamine receptors allow visualization and analysis of histamine receptors in the human brain (8-10). [C]Doxepin was synthesized and developed as a specific PET imaging agent for H receptors, showing strong and specific signals in the human brain (11). 3-(1-Imidazol-4-yl)propyl-4-fluorobenzyl ether (fluoroproxyfan) was found to be a potent and selective HR antagonist (10). [F]Fluoroproxyfan was synthesized and evaluated as a specific PET imaging tool for HRs (12).