Synthesis and evaluation of 2-(3'-iodo-4'-aminophenyl)-6-hydroxybenzothiazole for in vivo quantitation of amyloid deposits in Alzheimer's disease.

Abstract

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.

• Authors: Yanming Wang, William E Klunk, Guo-Feng Huang, Manik L Debnath, Daniel P Holt, Chester A Mathis
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) 2002 Aug-Oct Vol. 19 Issue 1-2 Pg. 11-6 ISSN: 0895-8696 [Print] United States
• PMID: 12212766 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-(3'-iodo-4'-aminophenyl)-6-hydroxybenzothiazole
• 2-(4'-dimethylaminophenyl)-6-iodobenzoxazole
• Amyloid beta-Peptides
• Aniline Compounds
• Benzothiazoles
• Benzoxazoles
• Iodine Radioisotopes
• Radiopharmaceuticals
• Thiazoles
• benzothiazole

Topics

• Alzheimer Disease (diagnostic imaging, metabolism)
• Amyloid beta-Peptides (analysis)
• Aniline Compounds (chemical synthesis)
• Animals
• Benzothiazoles
• Benzoxazoles (chemical synthesis)
• Brain (diagnostic imaging, metabolism)
• Evaluation Studies as Topic
• Humans
• Iodine Radioisotopes
• Mice
• Neurofibrillary Tangles (diagnostic imaging, metabolism)
• Protein Binding
• Radiopharmaceuticals (chemical synthesis)
• Thiazoles (chemical synthesis)
• Tomography, Emission-Computed, Single-Photon (methods)