Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): development of ligands with optimized lipophilicity and binding affinity.

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Fan H, Kotsikorou E, Hoffman AF, Ravert HT, Holt D, Hurst DP, Lupica CR, Reggio PH, Dannals RF, Horti AG

Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): development of ligands with optimized lipophilicity and binding affinity.

Eur J Med Chem. 2009 Feb;44(2):593-608. doi: 10.1016/j.ejmech.2008.03.040. Epub 2008 Apr 18.

PubMed ID

18511157 [ View in PubMed

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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.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rimonabant	Cannabinoid receptor 1	Ki (nM)	40	N/A	N/A	Details