It has been reported that bioisosteric replacement of an 1,2,4-oxadiazole ring by an 1,3,4-oxadiazole ring leads to higher polarity, reduced metabolic degradation by human liver microsomes and reduced interaction with hERG channels. In a seven to eight step synthesis 1,3,4-oxadiazles <b>9a-c</b> were synthesized as bioisosteric analogs of high-affinity but rather lipophilic CB<sub>2</sub> ligands <b>1a-c</b> containing an 1,2,4-oxadiazole ring. The 1,3,4-oxadiazole derivatives <b>9a</b> and <b>9b</b> show 10- and 50-fold reduced CB<sub>2</sub> affinity compared to the 1,2,4-oxadiazole derivatives <b>1a</b> and <b>1b</b>, respectively. However, the 1,3,4-oxadiazole <b>9a</b> has high CB<sub>2</sub> affinity (<i>K</i><sub>i</sub> = 25 nM) and high selectivity over the CB<sub>1</sub> receptor.