title: Characterization of [³H]Lu AE60157 ([³H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine₆ (5-HT₆) receptors in vivo.
abstract: The serotonin6 (5-HT(6)) receptor has received attention for its proposed role in cognitive impairments associated with schizophrenia and Alzheimer's disease. This has lead to a search for selective 5-HT(6) receptor ligands useful for in vivo imaging in animals and humans. The novel 5-HT(6) receptor antagonist Lu AE60157 (8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) displays high affinity for the human (h) 5-HT(6) receptor (K(d) 0.2nM), and broad profiling in 60 additional binding and enzyme assays showed that Lu AE60157 displays 16-fold selectivity to the h5-HT(2A) receptor (K(i) 3.2nM) and >100-fold selectivity to all other evaluated targets. Lu AE60157 was labeled with tritium in the N-methyl group and evaluated as a radioligand in vitro as well as in vivo in rats and mice. Autoradiography experiments showed that [(3)H]Lu AE60157 bound preferentially to rat brain regions with expected high 5-HT(6) receptor density. Furthermore, [(3)H]Lu AE60157 showed good brain penetration after systemic administration and high (about 75%) specific in vivo binding to the striatal 5-HT(6) receptor in rats. The striatal binding of [(3)H]Lu AE60157 was fully displaced by selective 5-HT(6) receptor antagonists (SB-742457; Lu AE58054) and antipsychotics known to inhibit the binding of 5-HT(6) receptors in vitro (clozapine; olanzapine; sertindole), but was not displaced by antipsychotics lacking high 5-HT(6) receptor affinities (risperidone; haloperidol; quetiapine). No specific binding to mouse brain tissue in vivo could be obtained. In conclusion, [(3)H]Lu AE60157 is suitable for measuring in vivo occupancies of 5-HT(6) receptor ligands in rat brain regions in which 5-HT(2A) receptors do not interfere.
authors.affiliation: Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, 9 Ottiliavej, Copenhagen-Valby, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Witten
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: Søren Møller
authors.initials: SM
authors.lastname: Nielsen
authors.forename: Silke
authors.initials: S
authors.lastname: Miller
authors.forename: Claus Tornby
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: Tine Bryan
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Lise Tøttrup
authors.initials: LT
authors.lastname: Brennum
authors.forename: Jørn
authors.initials: J
authors.lastname: Arnt
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D011485:Protein Binding; D011804:Quinolines / Q000378:metabolism*; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D015203:Reproducibility of Results; D012702:Serotonin Antagonists / Q000378:metabolism*; D013379:Substrate Specificity; D013450:Sulfones / Q000378:metabolism*
chemical_list: C572166:8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline; D008024:Ligands; D011804:Quinolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor