title: In vivo quantification of striatal dopamine D2 receptor occupancy by JNJ-37822681 using [11C]raclopride and positron emission tomography.
abstract: JNJ-37822681 is a novel, fast-dissociating dopamine D(2) receptor antagonist, currently in development as an antipsychotic drug candidate. A previous first-in-human study demonstrated mild central nervous system effects of JNJ-37822681 in healthy male volunteers. Significant but transient serum prolactin elevations were demonstrated, whereas other neurophysiological effects were relatively small. To investigate striatal dopamine D(2) receptor occupancy by variable single doses of JNJ-37822681, an open-label [(11)C]raclopride positron emission tomography study was performed in 12 healthy male volunteers, using the simplified reference tissue model with cerebellum as reference tissue. Oral administration of JNJ-37822681 resulted in dose-dependent dopamine D(2) receptor occupancy. Receptor occupancy increased from 9-19% at 2 mg doses to 60-74% at 20 mg doses of JNJ-37822681. Therefore, single oral doses of JNJ-37822681 can produce occupancy levels that are generally associated with clinical efficacy for registered antipsychotic drugs.
authors.affiliation: Centre for Human Drug Research, Zernikedreef 10, Leiden, The Netherlands. etbeek@chdr.nl
authors.forename: Erik T
authors.initials: ET
authors.lastname: te Beek
authors.forename: Peter
authors.initials: P
authors.lastname: de Boer
authors.forename: Matthijs
authors.initials: M
authors.lastname: Moerland
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schmidt
authors.forename: Nikie J
authors.initials: NJ
authors.lastname: Hoetjes
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cohen
authors.forename: Joop M A
authors.initials: JM
authors.lastname: van Gerven
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Lammertsma
mesh_terms: D000293:Adolescent; D000328:Adult; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D010880:Piperidines / Q000097:blood; D049268:Positron-Emission Tomography / Q000379:methods*; D011724:Pyridazines / Q000097:blood; D020891:Raclopride / Q000097:blood; D011869:Radioligand Assay / Q000379:methods; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D018492:Dopamine Antagonists; C576398:N-(1-(3,4-difluorobenzyl)piperidin-4-yl)-6-(trifluoromethyl)pyridazin-3-amine; D010880:Piperidines; D011724:Pyridazines; D017448:Receptors, Dopamine D2; D020891:Raclopride