Radiosynthesis and biodistribution in mice of a 18F-labeled analog of O-1302 for use in cerebral CB1 cannabinoid receptor imaging

Biol Pharm Bull. 2008 Jun;31(6):1274-8. doi: 10.1248/bpb.31.1274.

Abstract

The suitability of an 18F-labeled form of N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4'-(5-fluoropentyl)phenyl)-4-methyl-1H-pyrazole-3-carboxamide (1), a CB1 cannabinoid ligand with high binding affinity (Ki=0.91 nM) and moderate lipophilicity (log P7.4=2.9), as a radiotracer for positron emission tomography imaging was evaluated in mice. Ligand 1 was labeled with 18F (T1/2=109.7 min) by treatment of the corresponding tosyl derivative with [18F]fluoride ion in acetonitrile. Tissue distribution studies of the 18F-labeled form ([18F]1) in mice demonstrated low brain uptake with minimal specific binding in brain regions. Cyclosporin A (a modulator of P-glycoprotein) treatment significantly increased both the brain uptake and the brain-to-blood ratio of [18F]1, indicating the possibility that P-glycoprotein regulates the ability of [18F]1 to cross the blood brain barrier. Radioligand [18F]1 does not have the required properties for imaging the cerebral cannabinoid CB1 receptor in vivo.

MeSH terms

  • Animals
  • Biotransformation
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Brain / metabolism
  • Chromatography, Thin Layer
  • Cyclosporine / pharmacology
  • Fluorine Radioisotopes
  • Immunosuppressive Agents / pharmacology
  • Indicators and Reagents
  • Injections, Intravenous
  • Isotope Labeling
  • Male
  • Mice
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacokinetics*
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacokinetics*
  • Radionuclide Imaging
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / pharmacokinetics*
  • Receptor, Cannabinoid, CB1 / drug effects*
  • Tissue Distribution

Substances

  • Fluorine Radioisotopes
  • Immunosuppressive Agents
  • Indicators and Reagents
  • N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide
  • Piperidines
  • Pyrazoles
  • Radiopharmaceuticals
  • Receptor, Cannabinoid, CB1
  • Cyclosporine