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.
Chang
Young Soo
YS
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 110-744, South Korea.
Jeong
Jae Min
JM
Lee
Yun-Sang
YS
Kim
Hyung Woo
HW
Ganesha
Rai B
RB
Kim
Young Ju
YJ
Lee
Dong Soo
DS
Chung
June-Key
JK
Lee
Myung Chul
MC
D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D008024:Ligands; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics
D016229:Amyloid beta-Peptides; D005462:Fluorine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D013876:Thiophenes; C088015:benzothiophene