Synthesis, evaluation, and radiolabeling of new potent positive allosteric modulators of the metabotropic glutamate receptor 2 as potential tracers for positron emission tomography imaging

J Med Chem. 2012 Oct 25;55(20):8685-99. doi: 10.1021/jm300912k. Epub 2012 Oct 11.


The synthesis and in vitro and in vivo evaluation of a new series of 7-(phenylpiperidinyl)-1,2,4-triazolo[4,3-a]pyridines, which were conveniently radiolabeled with carbon-11, as potential positron emission tomography (PET) radiotracers for in vivo imaging of the allosteric binding site of the metabotropic glutamate (mGlu) receptor subtype 2 are described. The synthesized compounds proved to be potent and selective positive allosteric modulators (PAMs) of the mGlu receptor 2 (mGluR2) in a [³⁵S]GTPγS binding assay and were able to displace an mGluR2 PAM radioligand, which we had previously developed, with IC₅₀ values in the low nanomolar range. The most promising candidates were radiolabeled and subjected to biodistribution studies and radiometabolite analysis in rats. Preliminary small-animal PET (μPET) studies in rats indicated that [¹¹C]20f binds specifically and reversibly to an mGluR2 allosteric site, strongly suggesting that it is a promising candidate for PET imaging of mGluR2 in the brain.

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • CHO Cells
  • Carbon Radioisotopes
  • Cricetinae
  • Cricetulus
  • Humans
  • Male
  • Positron-Emission Tomography
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Radioligand Assay
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / pharmacokinetics
  • Radiopharmaceuticals / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate / metabolism*
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology
  • Tissue Distribution


  • Carbon Radioisotopes
  • Pyridines
  • Radiopharmaceuticals
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor 2