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

Rareş-Petru Moldovan; Kristin Hausmann; Winnie Deuther-Conrad; Peter Brust

doi:10.1021/acsmedchemlett.7b00129

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

ACS Med Chem Lett. 2017 Apr 28;8(5):566-571. doi: 10.1021/acsmedchemlett.7b00129. eCollection 2017 May 11.

Authors

Rareş-Petru Moldovan¹, Kristin Hausmann¹, Winnie Deuther-Conrad¹, Peter Brust¹

Affiliation

¹ Helmholtz-Zentrum Dresden-Rossendorf e.V., Institute of Radiopharmaceutical Cancer Research, Permoserstraße 15, Leipzig 04318, Germany.

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 (K_i(CB₂) = 0.29 nM) and selective (CB₁/CB₂ > 10000) CB₂ receptor ligands discovered so far, eligible for the development of an ¹⁸F-labeled PET radiotracer.

Keywords: Cannabinoid receptor type 2; binding affinity; fluorine; imidazole; positron emission tomography.