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JPET #202895 1) Title Page Monoamine Transporter Occupancy JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 JPETThis Fast article Forward. has not been Published copyedited andon formatted. May 29, The 2013 final asversion DOI:10.1124/jpet.112.202895 may differ from this version. JPET #202895 1) Title page Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboon and human using Positron Emission Tomography Robert A. Comley 1, Cristian A. Salinas 2, Mark Slifstein, Marcella Petrone 3, Carmine Marzano, Idriss Bennacef , Paul Shotbolt, Jasper Van der Aart 2, Marta Neve 3, Laura Iavarone, Roberto Gomeni 4, Marc Laruelle 5, Frank A. Gray, Roger N. Gunn 2, Eugenii A. Rabiner 2 Downloaded from Clinical Imaging Centre, GlaxoSmithKline, London, United Kingdom (R.A.C, C.A.S, C.M, I.B, P.S, J.V, R.N.G, M.L, E.A.R); Columbia University, New York, NY, USA (M.S); GlaxoSmithKline, Clinical Pharmacology Modelling and Simulation, Italy (M.P, M.N, L.L, R.G); GlaxoSmithKline, Clinical Pharmacology and Discovery Medicine, UK (F.G) jpet.aspetjournals.org at ASPET Journals on September 28, 2021 - 1 - Copyright 2013 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 This article has not been copyedited and formatted. The final version may differ from this version. JPET #202895 2) Running title page a) Occupancy of a novel triple reuptake inhibitor using PET b) Name: Eugenii Rabiner Address: Imanova Limited Burlington Danes Building, Downloaded from Imperial College London, Hammersmith Hospital, Du Cane Road, jpet.aspetjournals.org London, W12 0NN United Kingdom Phone: +44 20 8008 6042 at ASPET Journals on September 28, 2021 Fax: +44 20 8008 6491 E-mail: [email protected] c) Number of text pages: 32 Number of tables: 1 Number of figures: 2 Number of references: 48 Number of words in Abstract: 243 Number of words in Introduction: 544 Number of words in Discussion: 1130 d) BPND, In vivo PET binding potential, specific compared to nondisplaceable uptake; DAT: Dopamine reuptake transporter; MAOI, monoamine-oxidase inhibitor; MDD, Major Depressive Disorder; MRI, Magnetic Resonance Imaging; NET, Norepinephrine - 2 - JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 This article has not been copyedited and formatted. The final version may differ from this version. JPET #202895 reuptake inhibitor; Occ, occupancy; PET, Positron Emission Tomography; ROI, region of interest; SERT, Serotonin reuptake transporter; SNDRI, serotonin–norepinephrine– dopamine reuptake inhibitor; SSRI, serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TOC time-occupancy-curve; TRI, Triple reuptake inhibitor; VND, PET volume of distribution non-displaceable ligand in tissue relative to plasma; VT, PET volume of distribution total radioligand in tissue relative to plasma e) Recommended section assignment: Neuropharmacology Downloaded from jpet.aspetjournals.org at ASPET Journals on September 28, 2021 - 3 - JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 This article has not been copyedited and formatted. The final version may differ from this version. JPET #202895 3) Abstract Introduction: 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, optimising 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 is a novel TRI Downloaded from which until recently was under development for the treatment of major depressive disorder, its development having been put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and Methods: Papio transporter blockade (occupancy). Studies were performed in baboon ( jpet.aspetjournals.org Anubis) to determine the relationship between plasma concentration and occupancy of brain SERT, DAT and NET, using the radioligands [11C]DASB, [11C]PE2I, and [11C]MeNER (also known as [11C]MRB), and in human using [11C]DASB and [11C]PE2I. Results: In Papio Anubis plasma concentrations resulting in half maximal occupancy at at ASPET Journals on September 28, 2021 SERT, DAT and NET were found to be 15.16, 15.56 and 0.97 ng/ml respectively. In human, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. Conclusion: 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. - 4 - JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 This article has not been copyedited and formatted. The final version may differ from this version. JPET #202895 4) Introduction Triple reuptake inhibitors (TRI) are compounds designed to block the serotonin, nor- adrenaline and dopamine transporters, enhancing monoaminergic neurotransmission, and are seen as a promising advance in the treatment of neuropsychiatric disorders (Marks et al., 2008). GSK1360707 is a novel TRI which has been shown to be potent and selective, with excellent in vitro and in vivo profiles (see compound 17 in Micheli et al. (Micheli et al., 2010); for structure see (Teller and Furstner, 2011)). Downloaded from GSK1360707 was until recently being developed for the treatment of Major Depressive Disorder (MDD). Current therapies for MDD typically have response rates of 50-65% (Weinmann et al., 2008) and clinically meaningful activity only after 2 to 4 weeks jpet.aspetjournals.org (Montgomery, 1997). It is hypothesised that the blockade of the three mono-amine transporters will improve tolerability, speed of onset, response and/or remission rates. An effective TRI could reduce the need to use multiple psychoactive medications in at ASPET Journals on September 28, 2021 individual patients, an issue of concern given the lack of data on the effectiveness of drug-drug combinations, likely poor compliance (due to complex dosing regimens), the possibility of cumulative toxicity, and subsequent vulnerability to adverse events. In addition a TRI could have therapeutic potential in other diseases such as Parkinson’s disease (Hauser et al., 2007; Rascol et al., 2008), pain (Basile et al., 2007; Al-Shamahi et al., 2009), and obesity (Axel et al., 2010; Hansen et al., 2010; Sjodin et al., 2010). In contrast to the monoamine-oxidase inhibitors (MAOI) and tricyclic antidepressants (TCA), serotonin reuptake inhibitors (SSRIs) were synthesised and developed with a specific molecular target in mind; reaching the market in the late 1980s these drugs arguably represented the first major advance in the treatment of depression since the introduction of effective pharmacotherapy. However, despite their improved tolerability and safety profile, as compared to the TCA and MAOI, their efficacy and speed of therapeutic effect are not improved (as compared to the older agents). The observed - 5 - JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 This article has not been copyedited and formatted. The final version may differ from this version. JPET #202895 antidepressant effects of selective norepinephrine reuptake inhibitors (e.g. reboxetine), seemingly independent of serotonergic mechanisms, have led to the development of dual reuptake inhibitors (e.g. venlafaxine). More recently, the theory that enhanced dopaminergic neurotransmission may alleviate anhedonia, combined with evidence that several marketed antidepressants may possess pharmacologically relevant affinity for the DAT, has led to the development of TRI. The selection of a therapeutically meaningful dose of a novel pharmaceutical such as a Downloaded from TRI is a crucial step in early drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration and its target occupancy, optimising the dose selection process and reducing the time and jpet.aspetjournals.org cost of early phase drug development (Matthews et al., 2012). Here we present results of in vivo assessment of central monoamine reuptake transporter occupancy by GSK1360707, using PET. The aim of these studies was to at ASPET Journals on September 28, 2021 measure the degree of occupancy of SERT, DAT and NET in the brain, and to relate those measures to plasma concentrations. In doing so we also characterized the relationship between the plasma concentration time course and the transporter occupancy time course, which can be used to optimise the dose regimen and formulation of future clinical trials in order to stay within the anticipated therapeutic window (Nyberg et al., 1999). In the first instance pre-clinical imaging experiments were conducted to evaluate target occupancies in the proposed clinical dose range, before Phase 1 testing in humans. These data were then used to support the rationale for, and optimise the design of, a human dose-occupancy study (ClinicalTrials.gov identifier: NCT01153802) to obtain accurate estimates of PET IC50 values and support dose selection for subsequent clinical trials. - 6 - JPET Fast Forward. Published on May 17, 2013 as DOI: 10.1124/jpet.112.202895 This article has not been copyedited and formatted. The final version may differ from this version. JPET #202895 5) Methods Methods of quantification and test-rested variability for the radioligands used in this study have been previously reported in the literature; in brief, test-retest variability has been reported as <10% for [11C]DASB (Frankle et al., 2006); 9.2% to 15.6% for [11C]PE2I (DeLorenzo et al., 2009); and <10% for [11C]MRB (also known as [11C]MeNER) (Logan et al., 2007). Pre-clinical PET imaging studies Downloaded from PET imaging of the baboon (Papio Anubis) brain was performed at Columbia University Medical Center.
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