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Research ArticleNeuropharmacology

Monoamine Transporter Occupancy of a Novel Triple Reuptake Inhibitor in Baboons and Humans Using Positron Emission Tomography

Robert A. Comley, Cristian A. Salinas, Mark Slifstein, Marcella Petrone, Carmine Marzano, Idriss Bennacef, Paul Shotbolt, Jasper Van der Aart, Marta Neve, Laura Iavarone, Roberto Gomeni, Marc Laruelle, Frank A. Gray, Roger N. Gunn and Eugenii A. Rabiner
Journal of Pharmacology and Experimental Therapeutics August 2013, 346 (2) 311-317; DOI: https://doi.org/10.1124/jpet.112.202895
Robert A. Comley
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Cristian A. Salinas
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Mark Slifstein
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Marcella Petrone
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Carmine Marzano
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Idriss Bennacef
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Paul Shotbolt
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Jasper Van der Aart
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Marta Neve
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Laura Iavarone
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Roberto Gomeni
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Marc Laruelle
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Frank A. Gray
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Roger N. Gunn
Clinical Imaging Centre (R.A.C., C.A.S., C.M., I.B., P.S., J.V., M.L., R.N.G., E.A.R.) and Clinical Pharmacology and Discovery Medicine (F.G.) GlaxoSmithKline, London, United Kingdom; Columbia University, New York, New York (M.S.); and Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline, Verona, Italy (M.P, M.N., L.I., R.G.)
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Eugenii A. Rabiner
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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 [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.

Footnotes

    • Received January 17, 2013.
    • Accepted May 17, 2013.
  • ↵1 Current affiliation: F. Hoffmann-La Roche, Basel, Switzerland.

  • ↵2 Current affiliation: Imanova Limited, London, United Kingdom.

  • ↵3 Current affiliation: Aptuit, Verona, Italy.

  • ↵4 Current affiliation: Merck Research Laboratories, West Point, Pennsylvania.

  • ↵5 Current affiliation: Pharmacometrica, La Fouillade, France.

  • ↵6 Current affiliation: UCB S.A., Brussels, Belgium.

  • This work was funded by GlaxoSmithKline.

  • This work was previously presented at the following conferences: van der Aart J, Comley RA, Salinas CA, Slifstein M, Petrone M, Neve M, Iavarone LE, Gomeni RO, Gray FA, Gunn RN, et al. (2011) Estimation of in vivo selectivity of a triple monoamine reuptake inhibitor in non-human primate and human. BrainPET 2011: Xth International Conference on Quantification of Brain Function with PET; 2011 May 25–28; Barcelona, Spain; and Petrone M, Comley RA, Salinas CA, Neve M, Iavarone L, Gunn RN, Gomeni R, Rabiner E, and Gray FA (2010) Assessment of the occupancy-exposure relationship of a triple monoamine re-uptake inhibitor in human, using positron emission tomography. Sixth International Symposium on Measurement & Kinetics of In Vivo Drug Effects; 2010 April 21–24; Leiden, The Netherlands.

  • dx.doi.org/10.1124/jpet.112.202895.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 2
1 Aug 2013
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Research ArticleNeuropharmacology

Occupancy of a Novel Triple Reuptake Inhibitor Using PET

Robert A. Comley, Cristian A. Salinas, Mark Slifstein, Marcella Petrone, Carmine Marzano, Idriss Bennacef, Paul Shotbolt, Jasper Van der Aart, Marta Neve, Laura Iavarone, Roberto Gomeni, Marc Laruelle, Frank A. Gray, Roger N. Gunn and Eugenii A. Rabiner
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 311-317; DOI: https://doi.org/10.1124/jpet.112.202895

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Research ArticleNeuropharmacology

Occupancy of a Novel Triple Reuptake Inhibitor Using PET

Robert A. Comley, Cristian A. Salinas, Mark Slifstein, Marcella Petrone, Carmine Marzano, Idriss Bennacef, Paul Shotbolt, Jasper Van der Aart, Marta Neve, Laura Iavarone, Roberto Gomeni, Marc Laruelle, Frank A. Gray, Roger N. Gunn and Eugenii A. Rabiner
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 311-317; DOI: https://doi.org/10.1124/jpet.112.202895
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