In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously

Need, Anne B.; McKinzie, Jamie H.; Mitch, Charles H.; Statnick, Michael A.; Phebus, Lee A.

doi:10.1016/j.lfs.2007.09.005

Cited by 39 publications

(38 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lowest tracer dose that could be reliably quantified by LC-MS/MS was chosen (30 nmol/kg). A posttracer survival interval of 30 minutes was tested since it is commonly used in other preclinical occupancy experiments (Need et al, 2007;Nirogi et al, 2013). As it proved to give an appropriate ratio of total to nonspecific binding, this posttracer survival interval was chosen.…”

Section: Discussionmentioning

confidence: 99%

“…At each dose level, the animals were divided into two groups to investigate if C control was distinguishable from C nonspec . A post-tracer survival interval of 30 minutes was tested since it has been proven successful for several in vivo receptor occupancy methodologies (Need et al, 2007;Nirogi et al, 2013). For determination of tissue concentrations of tracer, the animals were injected via the tail vein with their groupspecific dose of tracer (n 5 3).…”

Section: Development Of a Pulmonary In Vivo Receptor Occupancy Methodmentioning

confidence: 99%

“…Calculation of Receptor Occupancy. Receptor occupancy calculations were made for each animal using a previously established method (Farde et al, 1988;Wadenberg et al, 2000;Need et al, 2007;Nirogi et al, 2013) described as follows:…”

Section: Data and Statistical Analysesmentioning

confidence: 99%

See 2 more Smart Citations

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

Boger

Ewing

Eriksson

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Investigation of pharmacokinetic/pharmacodynamic (PK/PD) relationships for inhaled drugs is challenging because of the limited possibilities of measuring tissue exposure and target engagement in the lung. The aim of this study was to develop a methodology for measuring receptor occupancy in vivo in the rat for the glucocorticoid receptor (GR) to allow more informative inhalation PK/PD studies. From AstraZeneca's chemical library ofpropoxy]indazol-1-yl]-N-methyl-benzamide] was identified to have properties that are useful as a tracer for GR in vitro. When given at an appropriate dose (30 nmol/kg) to rats, compound 1 functioned as a tracer in the lung and spleen in vivo using liquid chromatography-tandem mass spectrometry bioanalysis. The methodology was successfully used to show the dose-receptor occupancy relationship measured at 1.5 hours after intravenous administration of fluticasone propionate (20, 150, and 750 nmol/kg) as well as to characterize the time profile for receptor occupancy after a dose of 90 nmol/kg i.v. The dose giving 50% occupancy was estimated as 47 nmol/kg. The methodology is novel in terms of measuring occupancy strictly in vivo and by using an unlabeled tracer. This feature confers key advantages, including occupancy estimation not being influenced by drug particle dissolution or binding/dissociation taking place postmortem. In addition, the tracer may be labeled for use in positron emission tomography imaging, thus enabling occupancy estimation in humans as a translatable biomarker of target engagement.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Development Of a Pulmonary In Vivo Receptor Occupancy Methodmentioning

confidence: 99%

See 1 more Smart Citation

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

Boger

Ewing

Eriksson

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…We now report a new liquid chromatography-tandem mass spectrometry (LC-MS/ MS) based method for defining the occupancy of compounds at D 3 receptors after systemic dosing that enables simultaneous assessment of D 2 receptor occupancy by using this regional specificity. This method uses a nonlabeled tracer measured by LC-MS/MS, as previously reported for dopamine D 2 , NK 1 , 5HT 2A , and opioid receptors mu, kappa, and delta (Chernet et al, 2005;Barth et al, 2006;Need et al, 2007). In the present study, LC-MS/MS receptor occupancy data were used to guide investigation of the in vivo activities of two D 3 receptor antagonists, SB-277011A and U99194.…”

Section: Introductionmentioning

confidence: 97%

In Vivo Occupancy of Dopamine D₃ Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder

Barth¹,

Need²,

Tzavara³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Consistent with these findings, the D 3 receptor antagonists enhanced the acquisition of learning of rats either alone or in the presence of the norepinephrine uptake blocker reboxetine as with the attention-deficit-hyperactivity disorder (ADHD) drug methylphenidate. Like reboxetine, the D 3 receptor antagonists also prevented deficits induced by scopolamine in object recognition memory of rats. Mice in which the dopamine transporter (DAT) has been deleted exhibit hyperactivity that is normalized by compounds that are effective in the treatment of ADHD. Both D 3 receptor antagonists decreased the hyperactivity of DAT 2/2 mice without affecting the activity of wild type controls. The present findings indicate that dopamine D 3 receptor antagonists engender cognition-enhancing and hyperactivity-dampening effects. Thus, D 3 receptor blockade could be considered as a novel treatment approach for cognitive deficits and hyperactivity syndromes, including those observed in ADHD.

show abstract

“…Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) offers high sensitivity, excellent selectivity, automation, and superior accuracy in the detection and quantitation of trace analytes (11). LC-MS/MS is an alternative approach to radiolabeled methods for measuring receptor occupancy, and it has been successfully used in quantification of non-radiolabeled ligand (tracer) for dopamine D2, serotonin 5HT 2A , NK1, opiate, and histamine H 3 receptor occupancy in preclinical species (12)(13)(14)(15)(16)(17). It is a promising method to speed up the candidate screening process in high-throughput fashion as well as characterization of target expression by using LC-MS/MS characterization at a preclinical stage.…”

Section: Introductionmentioning

confidence: 99%

Mapping the Target Localization and Biodistribution of Non-Radiolabeled VMAT2 Ligands in rat Brain

Deng

Zhou

et al. 2014

AAPS J

View full text Add to dashboard Cite

Abstract. Imaging targeting vesicular monoamine transporter (VMAT2) alterations is a sensitive tool for early diagnosis of Parkinson's disease. Our group has reported several novel 2-amino-DTBZ derivatives as potential VMAT2 imaging agents. The objective of this paper is to develop a non-radiolabeled methodology to screen the candidate compounds for accelerating the drug discovery process. 9- Furthermore, several novel 2-amino-DTBZ derivatives were detected using this methodology, and their biodistribution data in rat brain were obtained. The information about target engagements of candidates was provided.

show abstract

In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously

Cited by 39 publications

References 24 publications

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

In Vivo Occupancy of Dopamine D₃ Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder

Mapping the Target Localization and Biodistribution of Non-Radiolabeled VMAT2 Ligands in rat Brain

Contact Info

Product

Resources

About

In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously

Cited by 39 publications

References 24 publications

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships

In Vivo Occupancy of Dopamine D3 Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder

Mapping the Target Localization and Biodistribution of Non-Radiolabeled VMAT2 Ligands in rat Brain

Contact Info

Product

Resources

About

In Vivo Occupancy of Dopamine D₃ Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder