Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1)

Development of ligands with optimized lipophilicity and binding affinity

Hong Fan, Evangelia Kotsikorou, Alexander F. Hoffman, Hayden T. Ravert, Daniel Holt, Dow P. Hurst, Carl R. Lupica, Patricia H. Reggio, Robert F Dannals, Andrew Horti

Research output: Contribution to journalArticle

Abstract

Cyano analogs of Rimonabant with high binding affinity for the cerebral cannabinoid receptor (CB1) and with optimized lipophilicity have been synthesized as potential positron emission tomography (PET) ligands. The best ligands of the series are optimal targets for the future radiolabeling with PET isotopes and in vivo evaluation as radioligands with enhanced properties for PET imaging of CB1 receptors in human subjects. Extracellular electrophysiological recordings in rodent brain slices demonstrated that JHU75528, 4, the lead compound of the new series, has functional CB antagonist properties that are consistent with its structural relationship to Rimonabant. Molecular modeling analysis revealed an important role of the binding of the cyano group with the CB1 binding pocket.

Original languageEnglish (US)
Pages (from-to)593-608
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume44
Issue number2
DOIs
StatePublished - Feb 2009

Fingerprint

rimonabant
Cannabinoid Receptor CB1
Positron emission tomography
Positron-Emission Tomography
Ligands
Imaging techniques
Lead compounds
Molecular modeling
Isotopes
Rodentia
Brain
4-cyano-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide

Keywords

  • Cannabinoid receptor
  • Carbon-11
  • JHU75528
  • Molecular modeling
  • Positron emission tomography
  • Receptor docking
  • Rimonabant

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1) : Development of ligands with optimized lipophilicity and binding affinity. / Fan, Hong; Kotsikorou, Evangelia; Hoffman, Alexander F.; Ravert, Hayden T.; Holt, Daniel; Hurst, Dow P.; Lupica, Carl R.; Reggio, Patricia H.; Dannals, Robert F; Horti, Andrew.

In: European Journal of Medicinal Chemistry, Vol. 44, No. 2, 02.2009, p. 593-608.

Research output: Contribution to journalArticle

Fan, Hong ; Kotsikorou, Evangelia ; Hoffman, Alexander F. ; Ravert, Hayden T. ; Holt, Daniel ; Hurst, Dow P. ; Lupica, Carl R. ; Reggio, Patricia H. ; Dannals, Robert F ; Horti, Andrew. / Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1) : Development of ligands with optimized lipophilicity and binding affinity. In: European Journal of Medicinal Chemistry. 2009 ; Vol. 44, No. 2. pp. 593-608.
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AU - Ravert, Hayden T.

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AU - Hurst, Dow P.

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