2. Academic Validation
  3. Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer

Rapid identification of a novel small molecule phosphodiesterase 10A (PDE10A) tracer

  • J Med Chem. 2012 May 24;55(10):4776-87. doi: 10.1021/jm3002372.
Essa Hu 1,  Ji Ma,  Christopher Biorn,  Dianna Lester-Zeiner,  Robert Cho,  Shannon Rumfelt,  Roxanne K Kunz,  Thomas Nixey,  Klaus Michelsen,  Silke Miller,  Jianxia Shi,  Jamie Wong,  Geraldine Hill Della Puppa,  Jessica Able,  Santosh Talreja,  Dah-Ren Hwang,  Stephen A Hitchcock,  Amy Porter,  David Immke,  Jennifer R Allen,  James Treanor,  Hang Chen
Affiliations

Affiliation

  • 1 Department of Small Molecule Chemistry, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. ehu@amgen.com
PMID: 22548439 DOI: 10.1021/jm3002372
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.

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