title: Receptor occupancy and brain free fraction.
abstract: This study was designed to investigate whether brain unbound concentration (C(u,brain)) is a better predictor of dopamine D(2) receptor occupancy than total brain concentration, cerebrospinal fluid concentration (C(CSF)), or blood unbound concentration (C(u,blood)). The ex vivo D(2) receptor occupancy and concentration-time profiles in cerebrospinal fluid, blood, and brain of six marketed antipsychotic drugs were determined after oral administration in rats at a range of dose levels. The C(u,brain) was estimated from the product of total brain concentration and unbound fraction, which was determined using a brain homogenate method. In conclusion, the C(u,brain) of selected antipsychotic agents is a good predictor of D(2) receptor occupancy in rats. Furthermore, C(u,brain) seems to provide a better prediction of D(2) receptor occupancy than C(CSF) or C(u,blood) for those compounds whose mechanism of entry into brain tissue is influenced by factors other than simple passive diffusion.
authors.affiliation: Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, Scotland, UK.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Watson
authors.forename: Sara
authors.initials: S
authors.lastname: Wright
authors.forename: Adam
authors.initials: A
authors.lastname: Lucas
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Clarke
authors.forename: Jean
authors.initials: J
authors.lastname: Viggers
authors.forename: Sharon
authors.initials: S
authors.lastname: Cheetham
authors.forename: Phil
authors.initials: P
authors.lastname: Jeffrey
authors.forename: Rod
authors.initials: R
authors.lastname: Porter
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D008297:Male; D020891:Raclopride / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D017448:Receptors, Dopamine D2; D020891:Raclopride