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 [(11)C]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 (11)C, longer lived (18)F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [(18)F]fluoroethoxy-substituted benzothiazole derivatives ([(18)F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [(18)F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [(18)F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [(18)F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [(18)F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [(18)F]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.
Neumaier
B
B
Department of Nuclear Medicine, University of Ulm, Ulm, Germany. bernd.neumaier@nf.mpg.de
Deisenhofer
S
S
Sommer
C
C
Solbach
C
C
Reske
S N
SN
Mottaghy
F
F
D000544:Alzheimer Disease / Q000000981:diagnostic imaging; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D005462:Fluorine Radioisotopes; D051379:Mice; D016513:Mice, SCID; D058225:Plaque, Amyloid / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics
C550256:2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole; D000682:Amyloid; D052160:Benzothiazoles; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals