Synthesis, radiolabeling and in vivo evaluation of [(11)C](R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, a potential PET radioligand for the 5-HT(7) receptor

Eur J Med Chem. 2014 May 22:79:152-63. doi: 10.1016/j.ejmech.2014.03.066. Epub 2014 Mar 29.

Abstract

In the search for a novel serotonin 7 (5-HT7) receptor PET radioligand we synthesized and evaluated a new series of biphenylpiperazine derivatives in vitro. Among the studied compounds, (R)-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol ((R)-16), showed the best combination of affinity, selectivity, and lipophilicity, and was thus chosen for carbon-11 labelling and evaluation in pigs. After intravenous injection, [(11)C](R)-16 entered the pig brain and displayed reversible tracer kinetics. Pretreatment with the 5-HT7 receptor selective antagonist SB-269970 (1) resulted in limited decrease in the binding of [(11)C](R)-16, suggesting that this radioligand is not optimal for imaging the brain 5-HT7 receptor in vivo but it may serve as a lead compound for the design of novel 5-HT7 receptor PET radioligands.

Keywords: 5-HT(7) receptor; Arylpiperazine; PET; Radioligand; SB-269970.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • CHO Cells
  • Carbon Isotopes
  • Cricetulus
  • HEK293 Cells
  • Humans
  • Kinetics
  • Ligands
  • Molecular Structure
  • Phenols / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Positron-Emission Tomography*
  • Propanols / chemical synthesis*
  • Propanols / chemistry
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Radiopharmaceuticals* / chemical synthesis
  • Radiopharmaceuticals* / pharmacokinetics
  • Receptors, Serotonin / metabolism*
  • Sulfonamides / pharmacology
  • Swine
  • Tissue Distribution

Substances

  • ((11)C)(R)-1-(4-(2-(4-methoxyphenyl)phenyl)piperazin-1-yl)-3-(2-pyrazinyloxy)-2-propanol
  • Carbon Isotopes
  • Ligands
  • Phenols
  • Piperazines
  • Propanols
  • Pyrazines
  • Radiopharmaceuticals
  • Receptors, Serotonin
  • SB 269970
  • Sulfonamides
  • serotonin 7 receptor