Rapid Identification of a Novel Small Molecule Phosphodiesterase 10A (PDE10A) Tracer
| Autor: | Dah-Ren Hwang, Geraldine Hill Della Puppa, Jamie Wong, Essa Hu, Thomas Nixey, Silke Miller, Hang Chen, Jessica Able, Dianna Lester-Zeiner, James J. S. Treanor, Robert Cho, Santosh Talreja, Roxanne Kunz, Jianxia Shi, Ji Ma, David C. Immke, Jennifer R. Allen, Christopher Biorn, Amy Porter, Klaus Michelsen, Shannon Rumfelt, Stephen Hitchcock |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Phosphodiesterase Inhibitors Aminopyridines Striatum In Vitro Techniques Tritium Permeability Cell Line Rats Sprague-Dawley Dogs Tandem Mass Spectrometry In vivo TRACER Drug Discovery Animals Humans Tissue Distribution ATP Binding Cassette Transporter Subfamily B Member 1 Radionuclide Imaging Phosphoric Diester Hydrolases Drug discovery Chemistry Brain Phosphodiesterase Stereoisomerism Surface Plasmon Resonance Molecular biology Small molecule Rats Pyridazines Rapid identification Quinolines Pyrazoles Molecular Medicine PDE10A Radiopharmaceuticals Chromatography Liquid Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 55:4776-4787 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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