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

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.

Positron Emission Tomographic Imaging of the Cannabinoid Type 1 Receptor System with [11C]OMAR ([11C]JHU75528): Improvements in Image Quantification Using Wild-Type and Knockout Mice

“…11 [ 11 C]MePPEP in mice also peaks before 90 minutes postinjection. 16 Taken together, the results of this study support the feasibility of using PET technology to study the CB1 receptor in vivo in the brain of genetically modified mice. Interestingly, [ 11 C]JHU75528 can be used to investigate the CB receptor system and assess the effect of new drugs and treatments in preclinical studies.…”

“…A recent study focused on reducing the lipophicity of the tracer [ 11 C]JHU75528. 16 The peak of radiotracer concentration occurred before 15 minutes postinjection. Our result was in accordance with the previously published data by Horti and colleagues using dissection methods, who reported a time to peak of 15 minutes postinjection (although there are no data on earlier time points).…”

Development of Radioligands for In Vivo Imaging of Type 1 Cannabinoid Receptors (CB1) in Human Brain

“…Extracellular electrophysiological recordings of rodent brain slices reveal that JHU75528 reverses the effects of the CB agonist WIN 55,212-2 on glutamate release in striatal brain slices. These data demonstrate that JHU75528 has functional CB antagonist properties, consistent with its structural relationship to Rimonabant [91].…”

“…The latest study of the Johns Hopkins group described a series of analogs of JHU75528 targeting a CB1 radioligand with high binding affinity and lower lipophilicity than that of JHU75528 [91] (Table 3). Several members of the series met the objective of the study.…”

Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease

“…This bond stabilizes the Lys192-Asp366 salt bridge in CB 1 helices 3 and 6, believed to be specific to the inactive CB 1 state (Lange & Kruse, 2005;McAllister et al, 2003). Rimonabant, through direct stacking of its 2,4-dichlorophenyl ring to the Trp279/Phe200/Trp356 residues (on CB 1 ) on one end and the para-chlorophenyl ring (on Rimonabant) to the Tyr275/Trp255/ Phe278 (on CB 1 ) on the other end, binds within the transmembrane-3-4-5-6 aromatic microdomain of the CB 1 (Fan et al, 2009;Lange & Kruse, 2005). These binding interactions with CB 1 seem to be important to Rimonabant's clinical efficacy to treat diabetes (Muccioli & Lambert, 2005) and a proposed mechanism is through increased insulin sensitivity in an age-dependent manner (Lipina et al, 2016) and oxidation of fatty acids in muscles and the liver (Patel & Pathak, 2007).…”