Synthesis and evaluation of benzothiophene derivatives as ligands for imaging beta-amyloid plaques in Alzheimer's disease.

The imaging of the distribution of beta-amyloid (Abeta) plaques in the brain is becoming an important diagnostic modality in Alzheimer's disease (AD). Here, we synthesized novel benzothiophene derivatives and labeled them with (18)F for the potential diagnostic imaging of AD patients using positron emission tomography. The K(i) values of benzothiophene derivatives were evaluated by competitive binding assay using 2-(3'-[(125)I]iodo-4'-N-methylaminophenyl)benzothiazole as a radioligand and Abeta(1-40) or Abeta(1-42) aggregates as receptors. All synthesized benzothiophene derivatives showed high binding affinities (K(i)=0.28-6.50 nM) to both Abeta(1-40) and Abeta(1-42) aggregates. Binding affinities were increased by O-alkylation or N-alkylation of 2-(4'-hydroxyphenyl)benzothiophene or 2-(4'-aminophenyl)benzothiophene. Biodistribution studies of 2-(4'-O-(2''-[(18)F]fluoroethyl)hydroxyphenyl)benzothiophene ([(18)F]) and 2-(4'-O-(3''-[(18)F]fluoropropyl)hydroxyphenyl)benzothiophene ([(18)F]) in normal mice were performed after intravenous injection through the tail vein. In biodistribution data, [(18)F] and [(18)F] showed high initial brain uptakes at 2 min (5.2+/-0.4% and 3.3+/-0.2% ID/g, respectively), and brain activities washed out to 2.0+/-0.2% and 0.5+/-0.1% ID/g at 4 h, respectively. In conclusion, benzothiophene derivatives showed excellent binding affinities for Abeta aggregates and high initial brain uptakes in normal mice.