title: BL-1020, a novel antipsychotic candidate with GABA-enhancing effects: D2 receptor occupancy study in humans.
abstract: BL-1020 is a potentially novel antipsychotic, which comprises the typical antipsychotic perphenazine linked by an ester bound to gamma-aminobutyric acid (GABA), intending a simultaneous dopamine-2 (D(2)) receptor blockade and GABA facilitation in the brain. This positron emission tomography (PET) study, using [(11)C]raclopride, assessed the extent and duration of D(2) receptor occupancy (D(2) RO) and safety for single doses of BL-1020 in healthy male subjects. Overall, this study did not raise any safety concern. Single doses of 16-32 mg BL-1020 caused a dose dependent striatal D(2) RO. The 32 mg dose of BL-1020 resulted in an average D(2) RO of 44% at 4-6 h post dosing (pd), which declined to 33% at 24 h pd. Equimolar doses of BL-1020 and perphenazine resulted in similar D(2) RO at 24 h pd. Pharmacokinetic-pharmacodynamic analysis predicted that oral once daily administration of 32 mg BL-1020 would result in D(2) ROs ranging from 52 to 66% at a steady state.
authors.affiliation: Uppsala Imanet AB, GE Healthcare, P.O. Box 967, Uppsala, Sweden. lieuwe.appel@ge.com
authors.forename: Lieuwe
authors.initials: L
authors.lastname: Appel
authors.forename: Yona
authors.initials: Y
authors.lastname: Geffen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heurling
authors.forename: Catarina
authors.initials: C
authors.lastname: Eriksson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Antoni
authors.forename: Shitij
authors.initials: S
authors.lastname: Kapur
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects*; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D010546:Perphenazine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D049268:Positron-Emission Tomography / Q000379:methods; D011388:Prolactin / Q000097:blood; D011485:Protein Binding / Q000187:drug effects; D020891:Raclopride / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D017448:Receptors, Dopamine D2; C539977:perphenazine GABA ester; D020891:Raclopride; D005680:gamma-Aminobutyric Acid; D011388:Prolactin; D010546:Perphenazine