Synthesis and evaluation of novel α-fluorinated (E)-3-((6-methylpyridin-2-yl)ethynyl)cyclohex-2-enone-O-methyl oxime (ABP688) derivatives as metabotropic glutamate receptor subtype 5 PET radiotracers

J Med Chem. 2012 Aug 23;55(16):7154-62. doi: 10.1021/jm300648b. Epub 2012 Aug 9.

Abstract

In the search for an optimal fluorine-18-labeled positron emission tomography (PET) radiotracer for imaging metabotropic glutamate receptor subtype 5 (mGluR5), we have prepared a series of five α-fluorinated derivatives based on the ABP688 structural manifold by application of a two-step enolization/NFSI α-fluorination method. Their binding affinities were evaluated in vitro, and the most promising candidate (Z)-16 exhibited a K(i) of 5.7 nM and a clogP value of 2.3. The synthesis of the precursor tosylate (E)-22 revealed a preference for the (E)-configurational isomer (K(i) = 31.2 nM), and successful radiosynthesis afforded (E)-[(18)F]-16 which was used as a model PET tracer to establish plasma and PBS stability. (E)-[(18)F]-16 (K(d) = 70 nM) exhibited excellent specificity for mGluR5 in autoradiographic studies on horizontal rat brain slices in vitro.

MeSH terms

  • Animals
  • Autoradiography
  • Binding, Competitive
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Crystallography, X-Ray
  • Fluorine Radioisotopes
  • In Vitro Techniques
  • Oximes / chemical synthesis*
  • Oximes / chemistry
  • Oximes / metabolism
  • Positron-Emission Tomography
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime
  • Fluorine Radioisotopes
  • Grm5 protein, rat
  • Oximes
  • Pyridines
  • Radiopharmaceuticals
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate