Synthesis and evaluation of 18F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [C-11]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of C-11, longer lived F-18-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [F-18]fluoroethoxy-substituted benzothiazole derivatives ([F-18]2-(4'(methylamino)pheny1)-6-(2-fluoroethoxy)benzothiazole, [F-18]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [F-18]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [F-18]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [F-18]2-(4'(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [F-18]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity. (C) 2010 Elsevier Ltd. All rights reserved.