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.
D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005260:Female; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry*; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D058225:Plaque, Amyloid / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000378:metabolism; D011877:Radionuclide Imaging; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
D007457:Iodine Radioisotopes; D008563:Membrane Lipids; D013844:Thiazoles