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

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4893-4898. doi: 10.1016/j.bmcl.2015.05.080. Epub 2015 Jun 1.

Abstract

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 [(11)C]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.

Keywords: Huntington’s disease; Imaging; PDE10A; PET tracer; Phosphodiesterase 10A; Positron emission tomography; Schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Macaca mulatta
  • Models, Molecular
  • Molecular Structure
  • 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
  • Structure-Activity Relationship

Substances

  • Carbon Radioisotopes
  • Heterocyclic Compounds, 2-Ring
  • MK-8193
  • Phosphodiesterase Inhibitors
  • Phosphoric Diester Hydrolases