Pyrrolovesamicols--synthesis, structure and VAChT binding of two 4-fluorobenzoyl regioisomers

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2163-6. doi: 10.1016/j.bmcl.2012.01.127. Epub 2012 Feb 4.

Abstract

This Letter describes the synthesis of two regioisomers of a new class of vesamicol analogs as possible ligands for imaging the vesicular acetylcholine transporter in future PET studies. The two pyrrolovesamicols (±)-6a and (±)-6b were synthesized by nucleophilic ring opening reaction of a tetrahydroindole epoxide precursor with 4-phenylpiperidine. The reaction mechanism of the synthesis was studied by HPLC and the molecular structures were determined by X-ray structure analysis. Unexpected low binding affinities to VAChT (K(i)=312±73 nM for (±)-6a and K(i)=7320±1840 nM for (±)-6b) were determined by competitive binding analysis using a cell line stably transfected with ratVAChT and (-)-[(3)H]vesamicol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Contrast Media / chemical synthesis*
  • Contrast Media / metabolism
  • Crystallography, X-Ray
  • Epoxy Compounds / chemistry
  • Fluorine Radioisotopes
  • Humans
  • Ligands
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Positron-Emission Tomography
  • Pyrroles / chemical synthesis*
  • Pyrroles / metabolism
  • Rats
  • Stereoisomerism
  • Tritium
  • Vesicular Acetylcholine Transport Proteins / chemistry
  • Vesicular Acetylcholine Transport Proteins / metabolism*

Substances

  • Contrast Media
  • Epoxy Compounds
  • Fluorine Radioisotopes
  • Ligands
  • Piperidines
  • Pyrroles
  • Vesicular Acetylcholine Transport Proteins
  • Tritium
  • vesamicol
  • 4-phenylpiperidine