PT  - JOURNAL ARTICLE
AU  - Robert A. Comley
AU  - Cristian A. Salinas
AU  - Mark Slifstein
AU  - Marcella Petrone
AU  - Carmine Marzano
AU  - Idriss Bennacef
AU  - Paul Shotbolt
AU  - Jasper Van der Aart
AU  - Marta Neve
AU  - Laura Iavarone
AU  - Roberto Gomeni
AU  - Marc Laruelle
AU  - Frank A. Gray
AU  - Roger N. Gunn
AU  - Eugenii A. Rabiner
TI  - Monoamine Transporter Occupancy of a Novel Triple Reuptake Inhibitor in Baboons and Humans Using Positron Emission Tomography
AID  - 10.1124/jpet.112.202895
DP  - 2013 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 311--317
VI  - 346
IP  - 2
4099  - http://jpet.aspetjournals.org/content/346/2/311.short
4100  - http://jpet.aspetjournals.org/content/346/2/311.full
SO  - J Pharmacol Exp Ther2013 Aug 01; 346
AB  - 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 [11C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [11C]PE2I [N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane], and [11C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [11C]MRB) and in humans using [11C]DASB and [11C]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.