title: Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography.
abstract: The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.
authors.affiliation: Clinical Imaging Centre, GlaxoSmithKline, London, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Salinas
authors.forename: Mark
authors.initials: M
authors.lastname: Slifstein
authors.forename: Marcella
authors.initials: M
authors.lastname: Petrone
authors.forename: Carmine
authors.initials: C
authors.lastname: Marzano
authors.forename: Idriss
authors.initials: I
authors.lastname: Bennacef
authors.forename: Paul
authors.initials: P
authors.lastname: Shotbolt
authors.forename: Jasper
authors.initials: J
authors.lastname: Van der Aart
authors.forename: Marta
authors.initials: M
authors.lastname: Neve
authors.forename: Laura
authors.initials: L
authors.lastname: Iavarone
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
authors.forename: Frank A
authors.initials: FA
authors.lastname: Gray
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
mesh_terms: D000328:Adult; D000818:Animals; D053961:Azabicyclo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001596:Benzylamines / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009662:Nortropanes / Q000378:metabolism; D048530:Papio anubis; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D053961:Azabicyclo Compounds; D001596:Benzylamines; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009662:Nortropanes; D019275:Radiopharmaceuticals; D017367:Selective Serotonin Reuptake Inhibitors; C557997:1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo(4.1.0)heptane; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane