Development of Highly Affine and Selective Fluorinated Cannabinoid Type 2 Receptor Ligands

ACS Medicinal Chemistry Letters
Rareş-Petru MoldovanPeter Brust

Abstract

Cannabinoid type 2 receptors (CB2 receptors) are involved in various pathological processes, and the visualization of their in vivo availability with positron emission tomography (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB2 receptor ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compounds was developed by modifying (i) the adamantane-3-position, (ii) the imidazole-N-phenyl ring, and (iii) the imidazole-2-position, and the impact on the CB2 binding affinity and selectivity toward cannabinoid type 1 receptors (CB1) was evaluated. This study identified compound 15 as one of the most potent (Ki(CB2) = 0.29 nM) and selective (CB1/CB2 > 10000) CB2 receptor ligands discovered so far, eligible for the development of an (18)F-labeled PET radiotracer.

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Citations

Aug 23, 2018·Frontiers in Neurology·Paul EdisonMagdalena Sastre
Dec 26, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·João Franco MachadoJoão D G Correia
Jan 28, 2021·Journal of Medicinal Chemistry·Nerella Sridhar GoudPardeep Kumar

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