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[18F]-Labeled (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)-methanone.


Shan L.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Aug 24 [updated 2012 Sep 25].


[18F]-Labeled (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)-methanone, abbreviated as [18F]9, is a 2-aminoethylbenzofuran-based histamine subtype 3 receptor (H3R) antagonist/inverse agonist that was developed for imaging H3R with positron emission tomography (PET) (1). H3R is one of the four G-protein–coupled receptors of the histamine receptor family. The human H3R gene is located on chromosome 20q13.33, and its products are expressed predominantly in the basal ganglia, hippocampus, and cortical areas, which participate in the synthesis and release of neurotransmitters (e.g., acetylcholine, dopamine, serotonin, and noradrenaline) from histaminergic neurons (2-4). Imbalance of the histaminergic interactions results in a number of pathological states, which might be treated with H3R ligands as neuronal system modulators (5). To date, a large class of H3R ligands has been reported, which is either imidazole or non-imidazole in structure (1). These ligands have been applied to correct sleep and wakefulness disorders and narcolepsy (6). H3R antagonists have also been considered to be useful in correcting cognitive disorders and memory processes (7). However, there are many challenges for H3R ligand development because of the complexity of the central histaminergic system, the diversity of actions, and the overlapping pharmacology of H3R- and H4R-targeting compounds (5). H3R imaging with specific radioligands has the potential to elucidate changes in the distribution and density of H3R in living human brain and to determine the dose dependence of the extent and duration of H3R occupancy by candidates. In general, non-imidazole compounds appear more promising as radiotracers for H3R imaging. In an effort to develop an 18F-labeled H3R ligand, Bao et al. selected a new chemotype compound 9, a non-imidazole 2-aminoethylbenzofuran-based H3R antagonist/inverse agonist, for imaging feasibility evaluation in animals (1). Compound 9 has previously been shown to have a high affinity and selectivity for human H3R and to be able to cross the blood−brain barrier (8). In addition, compound 9 can be labeled with no-carrier-added fluorine-18 (t1/2 = 109.7 min) at an aryl carbon. The results obtained by Bao et al. have shown that [18F]9 is an effective radioligand for H3R imaging in mice and monkeys (1).

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