Abstract
A radiolabeled tracer for imaging therapeutic targets in the brain is a valuable tool for lead optimization in CNS drug discovery and for dose selection in clinical development. We report the rapid identification of a novel phosphodiesterase 10A (PDE10A) tracer candidate using a LC-MS/MS technology. This structurally distinct PDE10A tracer, AMG-7980 (5), has been shown to have good uptake in the striatum (1.2% ID/g tissue), high specificity (striatum/thalamus ratio of 10), and saturable binding in vivo. The PDE10A affinity (K(D)) and PDE10A target density (B(max)) were determined to be 0.94 nM and 2.3 pmol/mg protein, respectively, using [(3)H]5 on rat striatum homogenate. Autoradiography on rat brain sections indicated that the tracer signal was consistent with known PDE10A expression pattern. The specific binding of [(3)H]5 to rat brain was blocked by another structurally distinct, published PDE10A inhibitor, MP-10. Lastly, our tracer was used to measure in vivo PDE10A target occupancy of a PDE10A inhibitor in rats using LC-MS/MS technology.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Aminopyridines / chemical synthesis*
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Aminopyridines / chemistry
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Aminopyridines / pharmacokinetics
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Animals
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Brain / diagnostic imaging
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Brain / enzymology
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Cell Line
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Chromatography, Liquid
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Dogs
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Humans
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In Vitro Techniques
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Male
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Permeability
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacokinetics
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Phosphoric Diester Hydrolases / metabolism*
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Protein Binding
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Pyrazoles / pharmacokinetics
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Pyridazines / chemical synthesis*
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Pyridazines / chemistry
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Pyridazines / pharmacokinetics
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Quinolines / pharmacokinetics
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Radionuclide Imaging
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Radiopharmaceuticals / chemical synthesis
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Radiopharmaceuticals / chemistry
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Radiopharmaceuticals / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Stereoisomerism
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Surface Plasmon Resonance
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Tandem Mass Spectrometry
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Tissue Distribution
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Tritium
Substances
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2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline
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5-(6,7-dimethoxycinnolin-4-yl)-N-isopropyl-3-methylpyridin-2-amine
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Aminopyridines
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyridazines
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Quinolines
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Radiopharmaceuticals
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Tritium
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PDE10A protein, human
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PDE10A protein, rat
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Phosphoric Diester Hydrolases