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 1-123/125-labelling for single photon emission computed tomography (SPECT) imaging. In this study, we report the synthesis and 1-125-radiolabelling of Compound 6 and its in vitro and in vivo properties. Compound 6 [2-(3′-iodo-4′-aminophenyl)-6-hydroxybenzothiazole] bound to synthetic Aβ_(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 Aβ_(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.