Tricyclic Fused Pyrazoles with a ‘Click’ 1,2,3-Triazole Substituent in Position 3 Are Nanomolar CB₁ Receptor Ligands

Abstract

Structural modification of the potent conformationally constrained tricyclic pyrazole CB₁ ligand NESS0327 was achieved by replacing: (1) the chlorine substituent on the tricycle with a 3-fluoropropyl chain, and (2) the pyrazole 3-{[(piperidino)amino]carbonyl} substituent with a 4-substituted 1,2,3-triazole group obtained by click chemistry from an alkynyl precursor. Among the resulting compounds, two are particularly promising candidates for [¹⁸F]radiolabelling and PET imaging studies of the CB₁ receptor, as they displayed K _i CB₁ = 62.5 nM and 42.5 nM, respectively, in the same range as that displayed by rimonabant.

Key words

cannabinoids - PET imaging - fluorine - Sonogashira reaction - click chemistry

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