Analogs of JHU75528, a PET ligand for imaging of cerebral cannabinoid receptors (CB1): development of ligands with optimized lipophilicity and binding affinity.
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.
PET Center, Division of Nuclear Medicine, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Hong
H
Fan
Evangelia
E
Kotsikorou
Alexander F
AF
Hoffman
Hayden T
HT
Ravert
Daniel
D
Holt
Dow P
DP
Hurst
Carl R
CR
Lupica
Patricia H
PH
Reggio
Robert F
RF
Dannals
Andrew G
AG
Horti
D001923:Brain Chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
C515663:4-cyano-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1