It was previously hypothesised that the sulphonamide moiety was the primary factor preventing the penetration of compounds 3 and 4 through the BBB due to the high MW and TPSA of the negatively charged species in vivo. Accordingly, we sought to replace this group with a less polar carbon-based scaffold despite its positive impact on receptor affinity. The crystal structure and interaction diagram also revealed a relatively large space without significant ligandreceptor interactions around the amino linker, which could be used to further adapt the physicochemical properties by incorporating unipolar structures without affecting the affinity too much. In the binding assay, compound 12 exhibited the highest affinity from all structures tested, with a nanomolar IC50 value that was comparable to that of AZD1283. Predictions from the CNS MPO and BBB scores also indicated brain permeability. Thus, candidate 12 was selected, radiolabelled and used for further evaluation. In vitro ARG blocking studies with ticagrelor demonstrated specificity for P2Y12R, but non-specific binding cannot be excluded.