Whereas the usage of the azetidine fragment results in higher CNS scores, the S score is similar to the piperazine and lower than the piperidine residue. The sulfonyl amide of AZD1283 5 displays a particularly strong interaction with the residues Lys280 and Arg256 (Figure and). A comparison with the predicted interaction profile of 6 in the binding pocket reveals that the omission of the sulfonyl amide group leads to weaker hydrogen bonds for these residues (-8.8 and -5.3 vs -3.6 and -4.2 kcal/mol) (Figure and) reflecting the difference in IC50 values of both compounds (Figure ). Nevertheless, a substitution of the sulfonyl amide with a less polar group is essential, because brain accessibility is severely limited by the strong hydrophilic nature of the sulphonyl group. Replacing the sulphonyl group in 5 with a methylene group and prolonging the carbon chain towards the aryl residue led to a significant decrease in hydrophilicity in compound 18 compared to 5, while maintaining a high docking score (-10.63 vs -10.44). In general compound 15-19 (-9.66--11.03) exhibited higher docking scores than the corresponding homologs 9-13 (-9.23--10.58) supporting the hypothesis that the methylene group replacement is beneficial for receptor affinity. The aryl moiety offers a feasible position for radiofluorination by means of nucleophilic aromatic substitution. Experiments with different substituents on the aromatic ring of AZD1283 demonstrated, that the addition of a fluorine substituent in position 4 had only a minor effect on the affinity. 32