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

The imaging of the distribution of β-amyloid (Aβ) 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 18F for the potential diagnostic imaging of AD patients using positron emission tomography. The Ki values of benzothiophene derivatives were evaluated by competitive binding assay using 2-(3′-[125I]iodo-4′-N-methylaminophenyl)benzothiazole as a radioligand and Aβ(1–40) or Aβ(1–42) aggregates as receptors. All synthesized benzothiophene derivatives showed high binding affinities (Ki=0.28–6.50 nM) to both Aβ(1–40) and Aβ(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″-[18F]fluoroethyl)hydroxyphenyl)benzothiophene ([18F]2c) and 2-(4′-O-(3″-[18F]fluoropropyl)hydroxyphenyl)benzothiophene ([18F]2d) in normal mice were performed after intravenous injection through the tail vein. In biodistribution data, [18F]2c and [18F]2d 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 Aβ aggregates and high initial brain uptakes in normal mice.