Synthesis and in vitro characterization of novel fluorinated derivatives of the TSPO 18 kDa ligand SSR180575

Eur J Med Chem. 2015 Aug 28:101:736-45. doi: 10.1016/j.ejmech.2015.07.033. Epub 2015 Jul 17.

Abstract

SSR180575 (1) is a high-affinity (0.83 nM) TSPO 18 kDa ligand belonging to the pyridazino[4,5-b]indole-1-acetamides family. Herein we describe the synthesis and in vitro characterization of two series of new fluorinated analogues. Eleven compounds (out of fifteen) displayed nanomolar to subnamolar affinities (0.30-8.1 nM) and high selectivities (Ki(CBR)/Ki(TSPO) > 10(3)). Two derivatives stand out as promising candidates for drug development or use as PET probes for in vivo neuroinflammation imaging, once fluorine-18-labelled.

Keywords: Neuroinflammation; Positron emission tomography; SSR180575; TSPO 18 kDa; pyridazino[4,5-b]indole-1-acetamides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry*
  • Acetamides / metabolism*
  • Animals
  • Brain / metabolism
  • Fluorine Radioisotopes / metabolism*
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / metabolism*
  • Inflammation / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Microsomes / chemistry
  • Microsomes / metabolism
  • Molecular Probes / chemical synthesis*
  • Molecular Probes / chemistry*
  • Molecular Probes / metabolism
  • Molecular Structure
  • Positron-Emission Tomography*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA / metabolism*

Substances

  • Acetamides
  • Bzrp protein, mouse
  • Fluorine Radioisotopes
  • Indoles
  • Molecular Probes
  • Receptors, GABA
  • SSR180575