Synthesis and evaluation in monkey of [(18)F]4-fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([(18)F]FIMX): a promising radioligand for PET imaging of brain metabotropic glutamate receptor 1 (mGluR1)

J Med Chem. 2013 Nov 27;56(22):9146-55. doi: 10.1021/jm4012017. Epub 2013 Nov 7.

Abstract

We sought to develop a PET radioligand that would be useful for imaging human brain metabotropic subtype 1 receptors (mGluR1) in neuropsychiatric disorders and in drug development. 4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide (FIMX, 11) was identified as having favorable properties for development as a PET radioligand. We developed a method for preparing [(18)F]11 in useful radiochemical yield and in high specific activity from [(18)F]fluoride ion and an N-Boc-protected (phenyl)aryliodonium salt precursor (15). In baseline experiments in rhesus monkey, [(18)F]11 gave high brain radioactivity uptake, reflecting the expected distribution of mGluR1 with notably high uptake in cerebellum, which became 47% lower by 120 min after radioligand injection. Pharmacological challenges demonstrated that a very high proportion of the radioactivity in monkey brain was bound specifically and reversibly to mGluR1. [(18)F]11 is concluded to be an effective PET radioligand for imaging mGluR1 in monkey brain and therefore merits further evaluation in human subjects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Macaca mulatta
  • Positron-Emission Tomography / methods*
  • Radiochemistry
  • Receptors, Metabotropic Glutamate / metabolism*
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry

Substances

  • 4-fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide
  • Benzamides
  • Ligands
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • metabotropic glutamate receptor type 1