Synthesis and evaluation of 2-(3'-iodo-4'-aminophenyl)-6-hydroxybenzothiazole for in vivo quantitation of amyloid deposits in Alzheimer's disease.
A potent and brain permeable amyloid ligand has been identified as a lead compound capable of I-123/125-labelling for single photon emission computed tomography (SPECT) imaging. In this study, we report the synthesis and I-125-radiolabelling of Compound 6 and its in vitro and in vivo properties. Compound 6 [2-(3'-iodo-4'-aminophenyl)-6-hydroxybenzothiazole] bound to synthetic A beta(1-40) fibrils in a saturable manner, exhibiting an affinity (Ki) of 11+/-1.1 nM in a competitive binding assay using a tritiated thioflavin T analog ([3H]BTA-1) as radioligand. [125I]6 binding to synthetic A beta(1-40) fibrils fit a single-site model. [125I]6 exhibited several-fold higher binding to homogenates of frontal cortex from post-mortem Alzheimer's disease brain relative to age-matched control brain homogenates. No difference in binding was observed in cerebellum. The ratio of radioactivity concentration between frontal cortex and cerebellum was 6-fold higher in AD brain homogenates than the age-matched control. [125I]6 also readily penetrated the blood-brain barrier in normal control mice with an average radioactivity concentration of 6.43+/-0.62%ID/g detected in the whole brain at 2 min post i.v. injection. At 30 min, the radioactivity concentration decreased to 0.40+/-0.05%ID/g, indicating good clearance in the absence of amyloid deposits in the brain.
Wang
Yanming
Y
PET Facility, Department of Radiology, School of Medicine, University of Pittsburgh, PA 15213, USA. wangy2@msx.upmc.edu
Klunk
William E
WE
Huang
Guo-Feng
GF
Debnath
Manik L
ML
Holt
Daniel P
DP
Mathis
Chester A
CA
D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000814:Aniline Compounds / Q000138:chemical synthesis; D000818:Animals; D052160:Benzothiazoles; D001583:Benzoxazoles / Q000138:chemical synthesis; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005069:Evaluation Studies as Topic; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D016874:Neurofibrillary Tangles / Q000000981:diagnostic imaging* / Q000378:metabolism; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D013844:Thiazoles / Q000138:chemical synthesis; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
C470585:2-(3'-iodo-4'-aminophenyl)-6-hydroxybenzothiazole; C447161:2-(4'-dimethylaminophenyl)-6-iodobenzoxazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D001583:Benzoxazoles; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D013844:Thiazoles; C005465:benzothiazole