Effects of lipophilicity on the affinity and nonspecific binding of iodinated benzothiazole derivatives

Aseries of novel 2-aryl benzothiazole derivates substituted with iodine in different positions have been synthesized as amyloid-binding ligands. The affinity of these compounds for synthetic amyloid beta (1-40) (Abeta[1-40]) fibrils was determined. Introduction of the iodo group in the position ortho to an amino group increased the binding affinity, whereas the iodination ortho to a hydroxyl group decreased the binding affinity. Selected compounds with high binding affinity and moderate lipophilicity (logP values, 1.65-3.90) were radiolabeled and evaluated in normal mice for brain uptake and clearance. Structure-activity relationship (SAR) studies showed a strong correlation between the lipophilicity of the iodinated compounds and the binding affinity as well as nonspecific binding. As the lipophilicity increased, the affinity for Abeta(1-40) fibrils improved; however, nonspecific binding in mouse brain reflected by low brain clearance also increased with increasing lipophilicity. These results provide important SAR information to guide the development of novel amyloid-binding agents and provide further insights into the molecular interaction between 2-aryl benzothiazole ligands and Abeta fibrils.