In addition, glycogen synthase kinase 3 α (GSK3α) was identified as a potential off-target of a structurally related P2Y12R radioligand. TACs from PET analysis and brain radioactivity measured after ex vivo biodistribution indicated the anticipated brain uptake in WT mice which could be unambiguously confirmed by identification of intact tracer in the brain by ex vivo radio-HPLC. Hence, [ 18 F]12 is able to cross the BBB and has a favourable kinetic profile for neuroimaging. Further, ex vivo radio-HPLC revealed no radio-metabolites in the brain 60 min p.i., whereas in plasma, the fraction of intact tracer was strongly reduced indicative of a substantial tracer metabolization. AZD1283 was stopped in clinical studies, due to concerns about the metabolic stability of the ester group. In general, rapid tracer metabolism is undesirable, since it reduces the bioavailability of the intact tracer and generates radiometabolites with an unknown pharmacokinetic profile. The strong increase of polarity of the metabolites could hint towards esterase-catalyzed hydrolysis of the ester group to the corresponding carboxylic acid or may originate from hydrolysis of the nitrile or amide group, but also decreases the probability of brain uptake. Interestingly, Jackson et al. did not detect any metabolites derived from [ 11 C]AZD1283 in blood and liver 30 min p.i. This indicates that the replacement of the sulphonamide in [ 18 F]12 has an impact on the metabolic stability of the radiotracer in vivo. An interesting aspect is the low binding of the tracer to peripheral P2Y12R, which is predominantly expressed on blood platelets. The high metabolic rate of the tracer may explain low peripheral P2Y12R binding assuming ester cleavage as primary mechanism, because the resulting carboxylic acid showed a dramatically reduced target affinity for the P2Y12R. We were not able to quantify the fraction of platelet bound tracer in the blood.