Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand

Bioorg Med Chem. 2005 Nov 15;13(22):6188-94. doi: 10.1016/j.bmc.2005.06.030. Epub 2005 Jul 20.

Abstract

The novel pyrazolopyrimidine ligand, N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide 1 (DPA-713), has been reported as a potent ligand for the peripheral benzodiazepine receptor (PBR) displaying an affinity of K(i)=4.7 nM. In this study, 1 was successfully synthesised and demethylated to form the phenolic derivative 6 as precursor for labelling with carbon-11 (t(1/2) = 20.4 min). [11C]1 was prepared by O-alkylation of 6 with [11C]methyl iodide. The radiochemical yield of [(11)C]1 was 9% (non-decay corrected) with a specific activity of 36 GBq/micromol at the end of synthesis. The average time of synthesis including formulation was 13.2 min with a radiochemical purity >98%. In vivo assessment of [11C]1 was performed in a healthy Papio hamadryas baboon using positron emission tomography (PET). Following iv administration of [11C]1, significant accumulation was observed in the baboon brain and peripheral organs. In the brain, the radioactivity peaked at 20 min and remained constant for the duration of the imaging experiment. Pre-treatment with the PBR-specific ligand, PK 11195 (5 mg/kg), effectively reduced the binding of [11C]1 at 60 min by 70% in the whole brain, whereas pre-treatment with the central benzodiazepine receptor ligand, flumazenil (1mg/kg), had no inhibitory effect on [11C]1 uptake. These results indicate that accumulation of [11C]1 in the baboon represents selective binding to the PBR. These exceptional in vivo binding properties suggest that [11C]1 may be useful for imaging the PBR in disease states. Furthermore, [11C]1 represents the first ligand of its pharmacological class to be labelled for PET studies and therefore has the potential to generate new information on the pathological role of the PBR in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacokinetics
  • Acetamides / pharmacology*
  • Animals
  • Brain / anatomy & histology
  • Brain / diagnostic imaging*
  • Carbon Radioisotopes / chemistry
  • GABA-A Receptor Agonists*
  • Ligands
  • Male
  • Papio hamadryas
  • Positron-Emission Tomography / methods
  • Protein Binding
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Thorax / diagnostic imaging

Substances

  • Acetamides
  • Carbon Radioisotopes
  • GABA-A Receptor Agonists
  • Ligands
  • N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo(1,5-a)pyrimidin-3-yl)-acetamide
  • Pyrazoles
  • Pyrimidines