Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 and Fluorine-18 Labeled Reboxetine Analogues: Potential Positron Emission Tomography Radioligands for in Vivo Imaging of the Norepinephrine Transporter

Zeng, Fanxing; Mun, Ji-Young; Jarkas, Nashwa; Stehouwer, Jeffrey S.; Voll, Ronald J.; Tamagnan, Gilles; Howell, Leonard L.; Votaw, John R.; Kilts, Clinton D.; Nemeroff, Charles B.; Goodman, Mark M.

doi:10.1021/jm800817h

Cited by 30 publications

(30 citation statements)

References 45 publications

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“…The antidepressant desipramine also showed a similar potency to inhibit mouse NET (IC 50 9.4 Ϯ 5.8 nM; Table 3). (ϩ)-(S,S)-reboxetine showed potent inhibition for NET (Table 3) (IC 50 2.7 Ϯ 1.1 nM), findings that have been previously reported as well (Zeng et al, 2009). In HEK293 cells transiently expressing human NET, norZTP showed 16-fold more potent inhibi- Test substance concentration was 1 M. Positive substance concentration was 1 M for HOE140, endtoherin-1, leukotriene B 4 , leukotriene D 4 , and VIP; 100 M for Ro 16-6491; or 10 M for the others.…”

Section: Functional Assay For Norepinephrine and Serotoninsupporting

confidence: 85%

“…Pretreatment with reboxetine has been reported to have no effect on racropride-induced catalepsy in rats (Linnér et al, 2002). However, in our preliminary study, (ϩ)-(S,S)-reboxetine, an NRI with greater selectivity for NET than reboxetine (Wong et al, 2000;Zeng et al, 2009), significantly attenuated haloperidol-induced catalepsy with concomitant injection (unpublished observation). Taken together, these findings suggest that NET inhibition may contribute to catalepsy attenuation, and the NET inhibitory activity of norZTP may be involved in the unique in vivo profile demonstrated in the present study.…”

Section: Discussionmentioning

confidence: 61%

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Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Shobo

Yamada²,

Mihara³

et al. 2010

J Pharmacol Exp Ther

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The antipsychotic drug zotepine [ZTP;f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP;f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7-to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamineinduced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3␤,16␤,17␣,18␤,20␣)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in humans, norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.

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Section: Functional Assay For Norepinephrine and Serotoninsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 61%

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Shobo

Yamada²,

Mihara³

et al. 2010

J Pharmacol Exp Ther

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“…55 One such drug, reboxetine, provided a starting point for a PET study exploring possible effects of anaesthesia on radioligand binding by NET. 66 Using rhesus monkeys, PET studies of radiolabelled analogues of reboxetine were carried out in animals that were either awake or . ............................................................................................................................................... …”

Section: Norepinephrine Transportermentioning

confidence: 99%

Anaesthesia for positron emission tomography scanning of animal brains

Alstrup

Smith

2013

Lab Anim

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Positron emission tomography (PET) provides a means of studying physiological and pharmacological processes as they occur in the living brain. Mice, rats, dogs, cats, pigs and non-human primates are often used in studies using PET. They are commonly anaesthetized with ketamine, propofol or isoflurane in order to prevent them from moving during the imaging procedure. The use of anaesthesia in PET studies suffers, however, from the drawback of possibly altering central neuromolecular mechanisms. As a result, PET findings obtained in anaesthetized animals may fail to correctly represent normal properties of the awake brain. Here, we review findings of PET studies carried out either in both awake and anaesthetized animals or in animals given at least two different anaesthetics. Such studies provide a means of estimating the extent to which anaesthesia affects the outcome of PET neuroimaging in animals. While no final conclusion can be drawn concerning the 'best' general anaesthetic for PET neuroimaging in laboratory animals, such studies provide findings that can enhance an understanding of neurobiological mechanisms in the living brain. A new era of neuroscience began with the invention of positron emission tomography (PET) for studying processes as they occur in the living brain.1 -4 PET makes use of the radioactive decay of positron-emitting nuclides to derive an image of physiological and pharmacological events in a living organ such as the brain. PET is currently the primary procedure for studying molecular events in realtime in intact animals and humans. PET scanning can be used in all branches of pharmacology, molecular biology and medicine, including neuroscience, cancer research and cardiovascular biology. 5 -7

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“…Given the success of reboxetine analogs as NET ligands, Zeng and colleagues developed (2 S ,3 S )-2-[α-(2-methylphenoxy)phenylmethyl]morpholine (MENET) and radiolabeled it with 11 C to synthesize a radioligand with high affinity to NET while being selective against DAT and SERT [19, 20]. [ 11 C]MENET was used in vitro and in vivo in non-human primates.…”

Section: Introductionmentioning

confidence: 99%

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Adhikarla

Zeng

Votaw

et al. 2016

Nuclear Medicine and Biology

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Introduction Dysregulation of the noradrenergic system has been implicated in a number of neurological conditions such as Parkinson’s and Alzheimer’s. [11C]MENET is a novel PET radiotracer with high affinity and selectivity for the norepinephrine transporter. The applicability of different kinetic models on [11C]MENET PET image quantification in healthy population are evaluated. Methods Six healthy volunteers (mean age: 54 years) were recruited for the study, five of whom underwent arterial sampling for measurement of the input function. Ninety minute dynamic PET scans were obtained on a high resolution research tomograph with 15 mCi of [11C]MENET injected at the scan start time. Regions of interest were delineated on the PET scan aided by the corresponding MRI image for anatomical guidance. Distribution volumes and their ratios (DVRs) with respect to the occipital reference tissue were calculated using the full arterial model (FAM), the simplified reference tissue model (SRTM) and the multilinear reference tissue model (MRTM2). Results Among the FAMs, the single-tissue model was found to be statistically superior to the two-tissue model. [11C]MENET focal uptake was observed in the NET-rich regions of the brainstem and subcortical regions including the thalamus, locus cereleus and the raphe nuclei. Highest DVRs were observed in the locus cereleus (mean ± standard deviation: 1.39 ± 0.25) and red nucleus (1.35 ± 0.25). DVRs of the thalamus were in good agreement between FAM (1.26 ± 0.13), SRTM (1.23 ± 0.15) and MRTM2 (1.21 ± 0.14). Comparing the FAM to the SRTM and MRTM2, DVRs were underestimated in the thalamus by 3% and 4% on average, respectively. Conclusion The single-tissue compartmental model was sufficient in describing the [11C]MENET kinetics in the healthy human brain. SRTM and MRTM2 present themselves as attractive options for estimating NET DVR using an occipital reference region.

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Synthesis, Radiosynthesis, and Biological Evaluation of Carbon-11 and Fluorine-18 Labeled Reboxetine Analogues: Potential Positron Emission Tomography Radioligands for in Vivo Imaging of the Norepinephrine Transporter

Cited by 30 publications

References 45 publications

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Anaesthesia for positron emission tomography scanning of animal brains

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

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