N -(4-cyanotetrahydro-2 H -pyran-4-yl) and N -(1-cyanocyclohexyl) derivatives of 1,5-diarylpyrazole-3-carboxamides showing high affinity for 18 kDa translocator protein and/or cannabinoid receptors

In order to develop improved radioligands for imaging brain CB₁ receptors with positron emission tomography (PET) based on rimonabant (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl) -1H-pyrazole-3-carboxamide, 1), we synthesized compounds 9a-s in which the N-piperidinyl ring was replaced with a 4-(4-cyanotetrahydro-2H-pyranyl) or 1-cyanocyclohexyl ring. Such changes were expected to be almost isosteric with 1, confer greater metabolic resistance, and in the case of the 4-(4-cyanotetrahydro-2H-pyranyl) compounds, substantially reduce lipophilicity. One derivative, 1-(2-bromophenyl)-N-(1-cyanocyclohexyl)-5-(4-methoxyphenyl)-4- methylpyrazole-3-carboxamide (9n), showed high affinity (K_i = 15.7 nM) and selectivity for binding to CB₁ receptors. The corresponding 4-(4-cyanotetrahydro-2H-pyranyl) derivative (9m) also showed quite high affinity for CB₁ receptors (K_i = 62 nM) but was found to have even higher affinity (K_i = 29 nM) for the structurally unrelated 18 kDa translocator protein (TSPO). Some other minor structural changes among 9a-s were also found to switch binding selectivity from CB₁ receptors to TSPO or vice versa. These unexpected findings and their implications for the development of selective ligands or PET radioligands for CB₁ receptors or TSPO are discussed in relation to current pharmacophore models of CB₁ receptor and TSPO binding sites.