Discovery of [11C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors

[Display omitted] Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2015-11, Vol.25 (21), p.4893-4898
Hauptverfasser:	Cox, Christopher D., Hostetler, Eric D., Flores, Broc A., Evelhoch, Jeffrey L., Fan, Hong, Gantert, Liza, Holahan, Marie, Eng, Waisi, Joshi, Aniket, McGaughey, Georgia, Meng, Xiangjun, Purcell, Mona, Raheem, Izzat T., Riffel, Kerry, Yan, Youwei, Renger, John J., Smith, Sean M., Coleman, Paul J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Brain - metabolism Carbon Radioisotopes Crystallography, X-Ray Dose-Response Relationship, Drug Drug Discovery Heterocyclic Compounds, 2-Ring - chemical synthesis Heterocyclic Compounds, 2-Ring - chemistry Huntington’s disease Imaging Macaca mulatta Models, Molecular Molecular Structure PDE10A PET tracer Phosphodiesterase 10A Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - metabolism Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - blood Phosphoric Diester Hydrolases - metabolism Positron emission tomography Rats Schizophrenia Structure-Activity Relationship
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Zusammenfassung:	[Display omitted] Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [11C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2015.05.080