Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: Dopamine D2, serotonin 2A and NK-1 receptors as examples

Chernet, Eyassu; Martin, Laura J.; Li, Dominic; Need, Anne B.; Barth, Vanessa N.; Rash, Karen; Phebus, Lee A.

doi:10.1016/j.lfs.2005.04.075

Cited by 75 publications

(77 citation statements)

References 22 publications

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“…The ED 50 (dosage to reach 50% of plateau) was determined by nonlinear regression to arrive at a value of 200 6 12 mg/kg. The dosage of tracer used for studying target occupancy of testing a compound should not exceed 5% of occupancy by the tracer itself (Chernet et al, 2005). Therefore, 5 mg/kg of AMG 580 (with approximately 2.4% occupancy) was chosen for all of the subsequent studies.…”

Section: Resultsmentioning

confidence: 99%

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Chen

Lester-Zeiner

Shi

et al. 2014

J Pharmacol Exp Ther

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Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d] imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography-tandem mass spectrometry technology. [ 3 H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [18 F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies.

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Section: Resultsmentioning

confidence: 99%

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Chen

Lester-Zeiner

Shi

et al. 2014

J Pharmacol Exp Ther

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“…The mass spectrometry experiments used a novel technique in which the reporter molecule (MePPEP) was injected at low doses and subsequently measured in brain extracts with mass spectrometry (Chernet et al, 2005). The animals were pretreated with pharmacological doses (e.g., 10 mg/kg IV) of displacing agents 15 min before being injected with MePPEP (30 μg/ kg IV).…”

Section: Ex Vivo Mass Spectrometrymentioning

confidence: 99%

Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

et al. 2008

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Abstract[ 11 C]MePPEP is an inverse agonist and a radioligand developed to image cannabinoid CB 1 receptors with positron emission tomography (PET). It provides reversible, high specific signal in monkey brain. We assessed [ 11 C]MePPEP in rodent brain with regard to receptor selectivity, susceptibility to transport by P-glycoprotein (P-gp), sensitivity to displacement by agonists, and accumulation of radiometabolites. We used CB 1 receptor knockout mice and P-gp knockout mice to assess receptor selectivity and sensitivity to efflux transport, respectively. Using serial measurements of PET brain activity and plasma concentrations of [ 11 C]MePPEP, we estimated CB 1 receptor density in rat brain as distribution volume. CB 1 knockout mice showed only nonspecific brain uptake, and [ 11 C]MePPEP was not a substrate for P-gp. Direct acting agonists anandamide (10 mg/kg), methanandamide (10 mg/kg), CP 55,940 (1 mg/kg), and indirect agonist URB597 (0.3 and 0.6 mg/kg) failed to displace [ 11 C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg) displaced >65% of [ 11 C] MePPEP. Radiometabolites represented ∼13% of total radioactivity in brain between 30 and 120 min. [ 11 C]MePPEP was selective for the CB 1 receptor, was not a substrate for P-gp, and was more potently displaced by inverse agonists than agonists. The low potency of agonists suggests either a large receptor reserve or non-overlapping binding sites for agonists and inverse agonists. Radiometabolites of [ 11 C]MePPEP in brain caused distribution volume to be overestimated by ∼13%.

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“…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

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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.

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Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: Dopamine D2, serotonin 2A and NK-1 receptors as examples

Cited by 75 publications

References 22 publications

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

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

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Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: Dopamine D2, serotonin 2A and NK-1 receptors as examples

Cited by 75 publications

References 22 publications

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

AMG 580: A Novel Small Molecule Phosphodiesterase 10A (PDE10A) Positron Emission Tomography Tracer

Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

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

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