Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain

J Med Chem. 2012 Mar 8;55(5):2342-52. doi: 10.1021/jm201590g. Epub 2012 Feb 24.

Abstract

We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]6), 4-[(18)F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]7), and 4-[(18)F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]8), for imaging metabotropic glutamate receptor type 1 (mGluR1) in rodent brain. Unlabeled compound 6 was synthesized by benzoylation of 4-pyrimidinyl-2-methylaminothiazole 10, followed by reaction with isopropylamine. Removal of the methyl group in 6 gave phenol precursor 12 for radiosynthesis. Two fluoroalkoxy analogues 7 and 8 were prepared by reacting 12 with tosylates 13 and 14. Radioligands [(11)C]6, [(18)F]7, and [(18)F]8 were synthesized by O-[(11)C]methylation or [(18)F]fluoroalkylation of 12. Compound 6 showed high in vitro binding affinity for mGluR1, whereas 7 and 8 had weak affinity. Autoradiography using rat brain sections showed that [(11)C]6 binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study with [(11)C]6 in rats showed high brain uptake and a similar distribution pattern to that in autoradiography, indicating the usefulness of [(11)C]6 for imaging brain mGluR1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoradiography
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacokinetics
  • Brain / diagnostic imaging*
  • Brain / metabolism
  • Fluorine Radioisotopes
  • In Vitro Techniques
  • Isotope Labeling
  • Ligands
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Imaging
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry
  • Thiazoles / pharmacokinetics
  • Tissue Distribution

Substances

  • 4-fluoroethoxy-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide
  • 4-fluoropropoxy-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide
  • Benzamides
  • Fluorine Radioisotopes
  • Ligands
  • N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide
  • Radiopharmaceuticals
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor type 1