Synthesis and Evaluation of 11C-Labeled Imidazo[2,1-b]benzothiazoles (IBTs) as PET Tracers for Imaging β-Amyloid Plaques in Alzheimer's Disease

We report a novel series of C-11-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral beta-amyloid (A beta) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for A beta. Selected compounds were prepared as O- or N-[C-11]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[C-11]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([C-11]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for A beta(1-40) (K-i = 3.5 nM) and A beta(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PSI mouse model of AD (Tg), we demonstrate a specific uptake of [C-11]5 in A beta-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [C-11]5 and [H-3]1a together revealed that the tracers bind to A beta plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of A beta plaques.