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.
Triple reuptake inhibitors (TRIs) are compounds designed to block the serotonin, noradrenaline, 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 that has been shown to be potent and selective, with excellent in vitro and in vivo profiles [see compound 17 in Micheli et al. (2010); for structure, see Teller and Furstner (2011)].
Until recently, GSK1360707 was being developed for the treatment of major depressive disorder. Current therapies for major depressive disorders typically have response rates of 50–65% (Weinmann et al., 2008) and clinically meaningful activity only after 2 to 4 weeks (Montgomery, 1997). It is hypothesized that the blockade of the three monoamine transporters will improve tolerability, speed of onset, response, and remission rates. An effective TRI could reduce the need to use multiple psychoactive medications in individual patients, an issue of concern given the lack of data on the effectiveness of drug-drug combinations, likely poor compliance (owing 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 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 and tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs) were synthesized 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 compared with tricyclic antidepressants and monoamine-oxidase inhibitors, the efficacy and speed of SSRIs’ therapeutic effect are not improved compared with the older agents. The observed 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 TRIs.
The selection of a therapeutically meaningful dose of a novel pharmaceutical such as a TRI is a crucial step in early drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between plasma concentration and target occupancy, optimizing the dose selection process and reducing the time and cost of early phase drug development (Matthews et al., 2012).
Here we present the results of in vivo assessment, using PET, of central monoamine reuptake transporter occupancy by GSK1360707. The aim of these studies was to 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 optimize the dose regimen and formulation of future clinical trials to stay within the anticipated therapeutic window (Nyberg et al., 1999).
In the first instance, preclinical 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 optimize the design of, a human dose-occupancy study (clinicaltrials.gov identifier: NCT01153802) to obtain accurate estimates of IC50 values and support dose selection for subsequent clinical trials.
Materials and 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), 9.2–15.6% for [11C]PE2I (DeLorenzo et al., 2009), and <10% for [11C]MRB (also known as [11C]MeNER) (Logan et al., 2007).
Preclinical PET Imaging Studies
PET imaging of the baboon (Papio anubis) brain was performed at Columbia University Medical Center. All study procedures were approved by the Institutional Animal Care and Use Committees of Columbia University and the New York State Psychiatric Institute. Four male baboons were included in the study.
SERT and DAT occupancy were evaluated in three animals (A, B, and C) using the radioligands [11C]DASB and [11C]PE2I. NET occupancy was evaluated in three animals (A, C, and D) using the radioligand [11C]MeNER. The time-occupancy characteristics of GSK1360707 at the SERT and DAT were evaluated using an iterative approach, varying both the dose of GSK1360707 and the time of postdose scans, to characterize the time-dependent relationship between the plasma concentration of the drug and the target occupancy (time-occupancy curve, TOC). Evaluation of the NET occupancy was performed subsequent to the evaluation of the TOC at the SERT and DAT. Hence, the relationship between plasma concentration and NET occupancy was evaluated at one time point only (approximately the time of maximal brain concentration of GSK1360707). Since the relationship between plasma concentration and the occupancy at the SERT and DAT was determined to be direct (Derendorf and Meibohm, 1999), examination of the TOC at the NET was not considered essential.
Fasted animals were immobilized with ketamine (10 mg/kg i.m.). Anesthesia during preparation and scans was maintained with 2% isoflurane administered through an endotracheal tube. An intravenous catheter was inserted for radioligand administration, drug administration, and hydration. An arterial catheter was placed in a femoral artery for arterial blood sampling (including PK sampling) and continuous blood pressure monitoring. Vital signs (blood pressure, pulse, electrocardiogram, temperature, and respiration) were monitored continuously using a patient monitoring system (DataScope Corp, Paramus, NJ). Temperature was maintained at 37°C with a heated water blanket.
For all scanning sessions involving [11C]DASB and [11C]PE2I, acquisition of baseline scan data were followed by a constant intravenous infusion of GSK1360707 (formulated in saline and sodium hydroxide) lasting 30 minutes (up to a total dose per session of 0.125, 0.25, or 1 mg/kg, not exceeding 3 mg/kg for the study as a whole). The solution was delivered using a programmable syringe pump (Harvard Apparatus, Holliston, MA), followed by two postdrug PET scans (commencing between 0.25 and 10.75 hours after the end of the drug infusion). In general, doses were escalated from one session to the next; where this was not the case (to derive additional time-course data at a lower dose), a fresh baseline scan was acquired after an appropriate washout period. For each subject, scanning sessions (either single-scans post-GSK1360707 or two-scan sessions, including baseline and post-GSK1360707) were separated by a minimum of 7 days. [11C]MeNER scanning sessions were similar, with the exception of only a single scan that was acquired after the administration of GSK1360707 (0.25 hours after the end of the drug infusion).
[11C]DASB was prepared as previously described (Houle et al., 2000; Wilson et al., 2002). [11C]PE2I was prepared as in DeLorenzo et al. (2009). [11C]MeNER was prepared using a modification of the method in Lin and Ding (2004).
For each subject, a structural T1-weighted magnetic resonance brain scan was acquired on a GE 1.5-T Signa Advantage system (General Electric, Fairfield, CT) to aid identification of regions of interest (ROIs) for subsequent PET image analysis.
All PET scanning was performed on an HR+ scanner (Siemens, Knoxville, TN) operating in a three-dimensional mode. The animal’s head was placed in the center of the field of view, and a 10-minute transmission scan was acquired for attenuation correction, before tracer injection. Radioligands were administered as a 30-second i.v. bolus. Emission data were binned into a sequence of frames of increasing length. Total scan durations were 120 minutes for [11C]PE2I and [11C]MeNER and 90 minutes for [11C]DASB. PET data were corrected for attenuation, scatter, and random coincidences and reconstructed using filtered back-projection with a Shepp-Logan filter (cutoff 0.5 cycles per projection ray).
Arterial plasma samples were collected using an automated sampling system during the first 4 minutes (11 samples) and manually thereafter. A total of 22 for [11C]PE2I, 21 for [11C]DASB, and 22 for [11C]MeNER arterial samples were collected for input function measurement. Six additional samples were collected during each scan for high-performance liquid chromatography analysis of the unmetabolized fraction of radiotracer. During post-GSK1360707 scans, six additional venous samples were also collected (at 7, 15, 30, 60, 95, and 185 minutes after the radiotracer injection) for subsequent analysis of the plasma concentration of GSK1360707 by liquid chromatography-tandem mass spectrometry.
The ROIs were drawn manually on each animal’s MRI. The midbrain, thalamus, and striatum were defined as the target regions of interest for SERT; the striatum for DAT; and the midbrain, thalamus, and brainstem for NET. Dynamic PET data were corrected for motion and coregistered to each subject’s MRI using a mutual information cost function. Decay-corrected time activity curves were generated as the average ROI activity from each of the dynamically acquired PET frames.
Regional PET volume of distribution (VT) values for each ligand were derived from an appropriate compartmental model (one tissue for [11C]DASB, two tissues for [11C]PE2I and [11C]MeNER) with metabolite-corrected arterial plasma input function. For [11C]DASB and [11C]PE2I, regional binding potential (BPND) values were derived from the VT values, with the cerebellar VT assumed equal to the VND (nondisplaceable)). Target occupancy was derived as the fractional decrease of baseline BPND after the administration of GSK1360707. Occupancy values were averaged across all regions to provide an occupancy estimate for each postdose scan. Occupancy values derived in this way were compared with those derived using a simplified reference tissue model, which has been found to be acceptable for the quantification of [11C]DASB and [11C]PE2I data, since the latter would be used in the human experiments. As anticipated, the correlation was found to be acceptable, allowing the less invasive approach shown in eq. 1 to be taken in the human study:(1)
In the absence of a well characterized reference region for [11C]MeNER, a modified Lassen plot (Lassen et al., 1995; Cunningham et al., 2010) was used to estimate the VND and NET occupancy after each dose of GSK1360707.
Pharmacokinetic-Target Occupancy Analysis (Preclinical)
The PK/pharmacodynamic population consisted of a total seven measurements for SERT, eight for DAT, and seven for NET. Direct and indirect models were evaluated (for SERT and DAT). A modified Hill equation (a direct model) was found to describe the data adequately (indirect data not shown). The model (eq. 2), a semi-log form of the Hill equation, assumes that the maximal occupancy at a given target is 100% and the minimum occupancy is 0. This model was fitted to the whole data set using GraphPad Prism, version 5.03 (GraphPad Software, San Diego CA) to obtain estimates of half-maximal occupancy (IC50):(2)
Clinical PET Imaging Studies
Clinical studies were performed at the GlaxoSmithKline Clinical Imaging Centre, London. The study was approved by the Capenhurst Independent Research Ethics Committee (UK), and permission to administer radioisotopes was obtained from the Administration of Radioactive Substances Advisory Committee of the UK. Twelve healthy male subjects were enrolled into the study meeting the protocol inclusion and exclusion criteria posted on the ClinicalTrials.gov database (clinicaltrials.gov identifier: NCT01153802).
The aim of this study was to measure the time course of GSK1360707 occupancy at the SERT and DAT in the human brain after oral dosing and to relate those measures to plasma concentrations to investigate the relationship between the plasma concentration of GSK1360707 and its occupancy at each target. Human NET occupancy was not assessed.
Subjects were randomly assigned to one of two cohorts for the assessment of SERT and DAT occupancy.
Each subject received a baseline [11C]DASB or [11C]PE2I PET scan (PET scan 1). After a baseline scan, a single oral dose of GSK1360707 was administered, followed by two further PET scans (PET scans 2 and 3). PET scans 2 and 3 were used to provide information on the time course of brain SERT or DAT occupancy by GSK1360707. The time of PET scan 2 for the first two subjects was approximately 2 hours postdose (FTIH data indicated a plasma time of maximal concentration of 1.5–3 hours postdose for GSK1360707), and time of PET scan 3 was approximately 12 hours postdose based on observed human pharmacokinetics. For subsequent subjects, the dose (of GSK1360707) and timing of PET scans 2 and 3 were adjusted after review of the preceding subjects’ data to ensure an adequate sampling of the TOC using an adaptive design approach (Zamuner et al., 2010; Abanades et al., 2011). Subjects returned for a follow-up visit approximately 7 to 14 days after their last dose of study medication.
A range of doses of GSK1360707 was evaluated in this study (15–150 mg p.o.), after the demonstration of safety and tolerability in a previous placebo-controlled, single ascending dose study completed in healthy male subjects (report available at www.gsk-clinicalstudyregister.com, study identifier: SNV111914). Blood sampling was performed at the beginning of or immediately before each postdose PET scan. Quantification of plasma GSK1360707 was performed by liquid chromatography-tandem mass spectrometry, with the lower limit of quantification at 1 ng/ml.
[11C]DASB was prepared as described previously (Abanades et al., 2011).
[11C]PE2I was prepared as described in Supplemental Methods.
A structural T1-weighted magnetic resonance brain scan was acquired on a 3T MRI scanner (Siemens Tim Trio 3T; Siemens AG Medical Solutions, Erlangen, Germany). Data were acquired in the axial plane ((fast spoiled gradient-echo) – inversion-recovery-prepared, repetition time = 12.008, echo delay time = 5.1160, flip angle = 20°, slice thickness = 0.78 × 0.78 × 1.5 mm). All structural scans were inspected by an independent radiologist for unexpected findings of clinical significance.
All dynamic PET scans were acquired on a Siemens Biograph 6 PET/computed tomography scanner with TruePoint gantry (Siemens Healthcare). Subjects were positioned in the tomograph after insertion of a venous cannula in an antecubital vein, and a head-fixation device was used to minimize head movements during data acquisition. A low-dose computed tomography scan was performed before each injection of the radioligand for subsequent attenuation and scatter correction. Dynamic emission data were collected continuously for DASB (100 minutes) and PE2I (120 minutes) after intravenous injection of an average of 231 ± 56 MBq of [11C]DASB or 202 ± 82 MBq of [11C]PE2I. Image data were reconstructed using filtered back-projection with a 128 matrix, a zoom of 2.6, a transaxial Gaussian filter of 5 mm, scatter correction, and attenuation correction.
Imaging data were analyzed within the GSK Clinical Imaging Center molecular imaging analysis pipeline as previously described (Abanades et al., 2011). The midbrain, thalamus, and the striatum were defined as the target regions of interest for SERT and the striatum for DAT. The reference region time-activity curve derived from the cerebellum was used as an input to the simplified reference tissue model (Lammertsma and Hume, 1996) with a basis function implementation (Gunn et al., 1997), to quantify the binding potential (BPND) in all relevant target regions. Target occupancy in scans 2 and 3 was estimated as a fractional reduction in the relevant baseline BPND (see eq. 1).
Pharmacokinetic-Target Occupancy Analysis
The PK/pharmacodynamic populations for SERT and DAT occupancy consisted of 10 subjects, providing a total of 10 occupancy measurements for SERT and 8 for DAT. SERT occupancy values were derived by averaging across midbrain, striatum, and thalamus. Data were treated as previously described above for preclinical imaging experiments.
Preclinical PET Imaging Studies.
Four subjects provided data. The mean injected radioactivity for [11C]DASB, [11C]PE2I and [11C]MeNER were 160 ± 30, 155 ± 36, and 122 ± 44 MBq, respectively. The radiochemical purity of the injected [11C]DASB, [11C]PE2I, and [11C]MeNER exceeded 95% for all scans. The injected masses of cold DASB, PE2I, and MeNER varied between 0.43 and 1.22 μg (mean, 0.87 ± 0.29), 1.19 and 0.49μg (mean 0.84 ± 0.23), and 0.65 and 1.95 μg (mean, 0.86 ± 0.51), respectively. No serious adverse events were observed during the study. Results of PK-target occupancy modeling are shown in Fig. 1.
Clinical PET Imaging Studies.
A total of 10 evaluable subjects completed the study according to the protocol. The average age of the subjects was 42 years (range, 35–50), with a mean body mass index (BMI) of 27 kg/m2 (range, 23–29). The mean injected radioactivity was 231 ± 56 MBq for DASB and 221 ± 63 for PE2I. The radiochemical purity of the injected [11C]DASB and [11C]PE2I exceeded 95% for all scans. The injected masses of DASB and PE2I varied between 0.4 and 5.6 μg (mean 1.2 ± 1.2) and 0.4 and 6.3 μg (mean 1.9 ± 1.4), respectively. No serious adverse events were observed during the study. Results of PK-target occupancy modeling are shown in Fig. 2.
We conducted PET imaging experiments in P. anubis and humans to estimate in vivo IC50 (half-maximal target occupancy) of GSK1360707 for central SERT, DAT, and NET and to evaluate target occupancies in the likely clinical dose range. In P. Anubis, in vivo IC50 values for SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the values for SERT and DAT were 6.80 and 18.80 ng/ml.
In vitro studies previously demonstrated a dose-dependent occupancy of the SERT by GSK1360707, as well as the binding and blockade of functional responses at all three targets (compound 17 in Micheli et al., 2010). The rank order of pKi in binding assays was SERT > NET > DAT (Micheli et al., 2010). Our PET experiments in P. anubis suggest that the IC50 at SERT and DAT is equivalent and that the compound is more potent at NET (NET potency being judged in terms of the occupancy achieved at similar concentrations; since the NET IC50 estimate may not be reliable, see Discussion) (Table 1). This difference between in vitro data obtained using cells transfected with human transporters and the in vivo data from P. anubis could be due to species differences in the affinity of the transporters for GSK1360707 or because the in vitro assays do not adequately mimic the physiologic context of the in vivo environment.
PET studies in humans showed a clear separation in IC50 at SERT and DAT; the inconsistency compared with P. anubis was driven by a lower IC50 for SERT in humans, the IC50 for DAT was equivalent to that in P. anubis.
Clinical Context: Getting the “Right” Triple Profile.
Therapeutic effects at SERT are achieved after chronic treatment, generally when occupancy is ≥80% (Meyer et al., 2004). Therapeutic effects mediated by DAT inhibition are generally achieved when occupancy is in the region of 30% (Learned-Coughlin et al., 2003), with the high levels of DAT inhibition having been linked to the positive reinforcing effects and abuse liability of cocaine (Kuhar et al., 1991; Woolverton and Johnson, 1992).
Less is known about the level of NET inhibition required for the clinical efficacy of serotonin norepinephrine reuptake inhibitors. However, inhibition of NA uptake or ligand binding at NET has been demonstrated in vitro for a range of antidepressants and their metabolites (Pristupa et al., 1994; Owens et al., 1997; Tatsumi et al., 1997; Bymaster et al., 2001; Millan et al., 2001; Bymaster et al., 2002; Koch et al., 2003; Kuo et al., 2004; Vaishnavi et al., 2004), and maprotiline, desipramine, reboxetine, and to a lesser extent nortriptyline are highly selective for NET (above SERT and DAT). Paroxetine and venlafaxine act as NET antagonists in vivo at clinical doses (Gilmor et al., 2002; Davidson et al., 2005; Owens et al., 2008). In addition, it has been known for some time that the tricyclic antidepressant clomipramine occupies 80% of SERT at doses (and plasma concentrations) much lower than those used clinically (Suhara et al., 2003), suggesting a role for NET inhibition (via its active metabolite desmethylclomipramine (Thomas and Jones, 1977; Maj et al., 1982). Direct assessments of NET occupancy using PET have been made for nortriptyline, with a single dose of 75 mg (which is at the lower end of the clinically relevant range) producing in the region of 40% occupancy (Sekine et al., 2010). With respect to norepinephrine reuptake–mediated side effects, sibutramine, a serotonin norepinephrine reuptake inhibitor, was withdrawn from the market as a result of the level of adverse cardiovascular events (James et al., 2010). However, the dose of venlafaxine estimated to occupy 40% NET has minimal effects on heart rate and blood pressure. Taking all these factors into consideration, the ideal TRI profile is assumed to approximate to >70% SERT occupancy, 30–40% DAT occupancy, and 30% NET occupancy, providing efficacy with minimal DAT- and NET-mediated adverse events.
Profile of GSK1360707.
Human data indicate that it is possible to produce high levels of SERT occupancy (∼70%) with moderate DAT occupancy (∼30%–40%) at doses of GSK1360707 that are well tolerated. However, the question remains as to what the measured NET occupancy would be in this dose range. At the time the study was conducted, we did not have access to the NET ligand [11C]MeNER (for human use). GSK1360707 does appear to be more potent at NET (compared with the other targets) in P. anubis. However, the NET IC50 estimate is compromised by a lack of data at low occupancy levels, and because all doses tested were well tolerated in humans, with only one subject experiencing a clinically significant increase in heart rate and no subjects experiencing clinically significant changes in laboratory parameters or electrocardiographic results, the data obtained from P. anubis may not be predictive.
The discrepancy between data in P. anubis and that in humans reinforces the importance of human occupancy studies for decision making regarding compound progression and clinical dose selection.
Shortly after the conclusion of this study, development of GSK1360707 was put on hold after a decision by GlaxoSmithKline to exit certain research areas. It is difficult to predict how the clinical development of GSK1360707 would have progressed; however, based on the data presented here, it seems likely that the molecule would have progressed toward a proof-of-concept study, with the possible addition of an assessment of NET occupancy in human.
The assessment of NET IC50 in baboons is compromised by a lack of data at exposures resulting in low NET occupancy values.
The clinical part of our study was conducted in healthy male control subjects. Although we are not aware of any evidence to support this hypothesis, it is possible that physiologic or genetic factors (e.g., transporter polymorphisms) could differ in a patient group and affect in vivo IC50 values, for instance, differences in the affinity of the transporters, the concentration of GSK1360707 achieved in the brain, or endogenous neurotransmitter levels (such that a different level of transporter occupancy by the drug is required to raise endogenous neurotransmitter levels to the same degree). In addition, if a given occupancy level is achieved at the same plasma exposure, differences in second-messenger activity or the distribution and density of target or nontarget transporters could still modify the downstream response (e.g., NET blockade could raise dopamine levels in the prefrontal cortex, as DA is transported by NET in the absence of DAT, or differences in organic cation transporter or the plasma membrane monoamine transporter systems could affect clearance of biogenic amines.
For most patients, antidepressant response to SSRIs can be expected to occur with SERT blockade of >80%. We did not explore occupancy beyond that level in humans to avoid excessive modulation of any of the three targets, particularly DAT. This could result in inaccuracy in the IC50 estimates.
The authors thank Elizabeth Hackett, John Castrillon, and Sung A. Baall from Columbia University (data acquisition in the nonclinical studies); Balu Easwararmoorthy, also from Columbia University (chemistry for the nonclinical studies); Shaila Shabbir and Robert Lai from GlaxoSmithKline (clinical operations and medical monitoring); Gary Evoniuk, also from GlaxoSmithKline (comments on the manuscript); staff from the PAREXEL International Clinical Pharmacology research unit in Harrow; and the study participants.
Participated in research design: Comley, Salinas, Slifstein, Petrone, Shotbolt, Neve, Iavarone, Gomeni, Gray, Gunn, Rabiner.
Conducted experiments: Comley, Slifstein, Marzano, Bennacef, Shotbolt, Van der Aart, Rabiner.
Performed data analysis: Comley, Salinas, Slifstein, Petrone, Shotbolt, Neve, Iavarone, Gomeni, Gray, Gunn, Rabiner.
Wrote or contributed to the writing of the manuscript: Comley, Salinas, Slifstein, Petrone, Marzano, Shotbolt, Van der Aart, Neve, Iavarone, Gomeni, Gray, Gunn, Rabiner.
- 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.
- in vivo PET binding potential, specific compared with nondisplaceable uptake
- N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine
- dopamine reuptake transporter
- magnetic resonance imaging
- norepinephrine reuptake transporter
- positron emission tomography
- region of interest
- serotonin reuptake transporter
- serotonin reuptake inhibitor
- time-occupancy curve
- triple reuptake inhibitor
- PET volume of distribution nondisplaceable ligand in tissue relative to plasma
- PET volume of distribution total radioligand in tissue relative to plasma
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics