The central CB receptor represents a promising target for the treatment of neuroinflammatory diseases as CB activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [F]7a was reported, which shows high CB affinity and high selectivity over the CB subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a (K = 7.9 nM) and the ketone 26a (K = 8.6 nM) displayed high CB affinity and CB:CB selectivity in in vitro radioligand binding studies. Incubation of 7a, 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a, but a remarkably higher stability of ketone 26a in comparison to amide 7a. Furthermore, a logD value of 5.56 ± 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification.

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HCN4 channels are considered to be a promising target for cardiac pathologies, epilepsy, and multiple sclerosis. However, there are no subtype-selective HCN channel blockers available, and only a few compounds are reported to display subtype preferences, one of which is EC18 (cis-1). Herein, we report the optimized synthetic route for the preparation of EC18 and its evaluation in three different pharmacological models, allowing us to assess its activity on cardiac function, thalamocortical neurons, and immune cells.