Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using ( S , S )-[ 18 F]FMeNER-D 2 (original) (raw)
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NeuroImage, 2014
Background: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [ 11 C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [ 11 C]MRB (a NET ligand) and [ 11 C]AFM (a SERT ligand) to evaluate in vivo IC 50 values of ATX in monkeys. Methods: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2 h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12 mg/kg/h and 0.045-1.054 mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (V T) and IC 50 values were estimated. Results: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC 50 of 31 ± 10 and 99 ± 21 ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8 mg/kg, approx. 300-600 ng/mL plasma), ATX would occupy N 90% of NET and N 85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. Conclusion: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.
Journal of Nuclear Medicine, 2008
S,S)-18 F-FMeNER-D 2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. Methods: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-18 F-FMeNER-D 2 . Binding potential relative to nondisplaceable binding (BP ND ) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. Results: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BP ND values by the indirect kinetic method were 0.54 6 0.19 and 0.35 6 0.25 in the thalamus and locus coeruleus, respectively. BP ND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r 5 0.81-0.92). Conclusion: The regional distribution of (S,S)-18 F-FMeNER-D 2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.
Journal of Neurochemistry, 2005
We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with positron emission tomography (PET). Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P ¼ 1.0-3.5), high plasma free fraction and reasonable stability in plasma were selected for further studies. Based on our characterization studies in baboons, including 11 C-labeled (R)-nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and new analogs of methylreboxetine (MRB), in conjunction with our earlier evaluation of 11 C and 18 F derivatives of reboxetine, MRB and their individual (R,R) and (S,S) enantiomers, we have identified the superiority of (S,S)-[ 11 C]MRB and the suitability of MRB analogs [(S,S)-[ 11 C]MRB > (S,S)-[ 11 C]3-Cl-MRB > (S,S)-[ 18 F]fluororeboxetine] as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than in thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge (S,S)-[ 11 C]MRB remains by far the most promising NET ligand for PET studies.
NeuroImage, 2011
The objective of this study was to evaluate the suitability of [ 11 C]MRB for drug occupancy studies of NET using atomoxetine (ATX), a NET uptake inhibitor used in the treatment of depression and attention-deficit hyperactivity disorder (ADHD). A second goal of the study was identification of a suitable reference region. Ten PET studies were performed in three anesthetized rhesus monkeys following an infusion of ATX or placebo. [ 11 C]MRB arterial input functions and ATX plasma levels were also measured. A dosedependent reduction of [ 11 C]MRB volume of distribution was observed after correction for [ 11 C]MRB plasma free fraction. ATX IC 50 was estimated to be 31 ± 10 ng/mL plasma. This corresponds to an effective dose (ED 50) of 0.13 mg/kg, which is much lower than the therapeutic dose of ATX in ADHD (1.0-1.5 mg/kg). [ 11 C]MRB binding potential BP ND in the thalamus was estimated to be 1.8 ± 0.3. Defining a reference region for a NET radiotracer is challenging due to the widespread and relatively uniform distribution of NET in the brain. Three regions were evaluated for use as reference region: caudate, putamen and occipital cortex. Caudate was found to be the most suitable for preclinical drug occupancy studies in rhesus monkeys. The IC 50 estimate obtained using MRTM2 BP ND without arterial blood sampling was 21 ± 3 ng/mL (using caudate as the reference region). This study demonstrated that [ 11 C]MRB is suitable for drug occupancy studies of NET.
NeuroImage, 2008
S,S)-18 F-FMeNER-D 2 was recently developed as a radioligand for the measurement of norepinephrine transporter imaging with PET. In this study, a norepinephrine transporter was visualized in the human brain using this radioligand with PET and quantified by several methods. Methods: PET scans were performed on 10 healthy men after intravenous injection of (S,S)-18 F-FMeNER-D 2 . Binding potential relative to nondisplaceable binding (BP ND ) was quantified by the indirect kinetic, simplified reference-tissue model (SRTM), multilinear reference-tissue model (MRTM), and ratio methods. The indirect kinetic method was used as the gold standard and was compared with the SRTM method with scan times of 240 and 180 min, the MRTM method with a scan time of 240 min, and the ratio method with a time integration interval of 120-180 min. The caudate was used as reference brain region. Results: Regional radioactivity was highest in the thalamus and lowest in the caudate during PET scanning. BP ND values by the indirect kinetic method were 0.54 6 0.19 and 0.35 6 0.25 in the thalamus and locus coeruleus, respectively. BP ND values found by the SRTM, MRTM, and ratio methods agreed with the values demonstrated by the indirect kinetic method (r 5 0.81-0.92). Conclusion: The regional distribution of (S,S)-18 F-FMeNER-D 2 in our study agreed with that demonstrated by previous PET and postmortem studies of norepinephrine transporter in the human brain. The ratio method with a time integration interval of 120-180 min will be useful for clinical research of psychiatric disorders for estimation of norepinephrine transporter occupancy by antidepressants without requiring arterial blood sampling and dynamic PET.
European Journal of Nuclear Medicine and Molecular Imaging, 2008
Introduction (S,S)-[ 18 F]FMeNER-D 2 is a recently developed positron emission tomography (PET) ligand for in vivo quantification of norepinephrine transporter. A monkey occupancy study with the radioligand indicated that (S,S)-[ 18 F]FMeNER-D 2 can be useful for quantitative PET analysis. In this preliminary study, regional distributions in the living human brain were evaluated. Materials and methods Brain PET measurements were performed for a total of 255 min after the injection of 188.3± 5.7 MBq of (S,S)-[ 18 F]FMeNER-D 2 in four healthy male subjects. Regions of interests were drawn on the thalamus and the caudate in the coregistered MRI/PET images. Results (S,S)-[ 18 F]FMeNER-D 2 displayed good brain penetration and selective retention in regions rich in norepinephrine reuptake sites. The transient peak equilibrium was reached during the PET measurements. The ratios of radioactivity uptake in the thalamus to that in the caudate were 1.50±0.06 for the time period of 90-255 min. Conclusion The present preliminary investigation indicates that (S,S)-[ 18 F]FMeNER-D 2 has suitable characteristics for probing the norepinephrine reuptake system with PET in the human brain.
Neuropsychiatric Disease and Treatment, 2015
Attention deficit/hyperactivity disorder is one of the most common neurodevelopmental disorders. The pathophysiology is thought to involve noradrenaline and dopamine. The role of dopamine transporter (DAT) was evaluated in imaging studies using mostly dopamine reuptake inhibitors. Atomoxetine is a selective noradrenaline reuptake inhibitor. Here we report the results of a pilot study conducted to evaluate changes in striatal DAT after 8 weeks of atomoxetine treatment. Our results suggest that 8 weeks of atomoxetine treatment may change striatal DAT bioavailability as measured via SPECT but that change was not correlated with genotype or clinical improvement.
Journal of Pharmacology and Experimental Therapeutics, 2013
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)-2b-carbomethoxy-3b-(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. 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.
SEP-225289 Serotonin and Dopamine Transporter Occupancy: A PET Study
Journal of Nuclear …, 2011
SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An openlabel PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. Methods: Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n 5 7), 12 mg (n 5 5), and 16 mg (n 5 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using 11 C-N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methylphenyl) nortropane (11 C-PE2I) and 11 C-N,N-dimethyl-2-(2-amino-4cyanophenylthio)benzylamine (11 C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. Results: Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% 6 11% and 2% 6 13%, respectively, for 8 mg; 44% 6 4% and 9% 6 10%, respectively, for 12 mg; and 49% 6 7% and 14% 6 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC 50 (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. Conclusion: At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about indication, dose, and therapeutic potential.