Characterization of [3H]Lu AE60157 ([3H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine6 (5-HT6) receptors in vivo

The serotonin6 (5-HT6) 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-HT6 receptor ligands useful for in vivo imaging in animals and humans. The novel 5-HT6 receptor antagonist Lu AE60157 (8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) displays high affinity for the human (h) 5-HT6 receptor (Kd 0.2 nM), and broad profiling in 60 additional binding and enzyme assays showed that Lu AE60157 displays 16-fold selectivity to the h5-HT2A receptor (Ki 3.2 nM) 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 [3H]Lu AE60157 bound preferentially to rat brain regions with expected high 5-HT6 receptor density. Furthermore, [3H]Lu AE60157 showed good brain penetration after systemic administration and high (about 75%) specific in vivo binding to the striatal 5-HT6 receptor in rats. The striatal binding of [3H]Lu AE60157 was fully displaced by selective 5-HT6 receptor antagonists (SB-742457; Lu AE58054) and antipsychotics known to inhibit the binding of 5-HT6 receptors in vitro (clozapine; olanzapine; sertindole), but was not displaced by antipsychotics lacking high 5-HT6 receptor affinities (risperidone; haloperidol; quetiapine). No specific binding to mouse brain tissue in vivo could be obtained. In conclusion, [3H]Lu AE60157 is suitable for measuring in vivo occupancies of 5-HT6 receptor ligands in rat brain regions in which 5-HT2A receptors do not interfere.