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

A series 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 β (1–40) (Aβ[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 Aβ(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 Aβ fibrils.