Among the three crystal structures for P2Y12R provided by the protein data bank (PDB), the 4NJT structure was chosen for docking experiments, since it is co-crystallized with AZD1283 5. The quaternary structure of the receptor is characterized by a group of 7 transmembrane helices (TM), with the AZD1283 binding pocket located between TMIV and TMVII (Figure ). To analyse the structure-activity relationship between ligand and receptor, AZD1283 was formally divided into three fragments: the (hetero) aryl fragment Ar1, the amino linker and the aryl fragment Ar2 (Figure ). Using these substructures, we identified central interactions such as hydrogen bonding or π-π stacking using the drug discovery platform molecular operating environment (MOE) (Figure ). In order to pre-select the most promising structures for use as PET tracers, the proposed structures were limited to those that could be radiolabelled with fluorine-18. For docking experiments a set of potential P2Y12R ligands was generated, based on reported examples from literature as well as new motifs and substructures generated from scratch using MOE's Scaffold Replacement tool. The tracer candidates need to be able to cross the BBB in sufficient amounts. Thus, we used two different algorithms, the CNS MPO Score and the BBB Score , to assess the likelihood of brain permeability of the respective compound. In total, a set of 55 structures was tested in silico in docking studies (Table ). From these structures, compounds 5-22 were selected for structure-activity relationship (SAR) analysis, based on the docking score S and SAR results from literature (Table ). Also, they all exhibit promising BBB or CNS MPO scores for successful application as CNS drug. The 2D interaction diagram of the binding pocket shows tight hydrogen bonds for the ethyl 6-aminonicotinate backbone with the residues Tyr105, Tyr109, Asn159 and Cys194 (Figure and). The docking scores for the compounds 9/11/12 (-9.23 vs. -9.79 vs.