Synthesis and evaluation of 11C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as PET tracers for imaging β-amyloid plaques in Alzheimer's disease.

Abstract

We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) 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 Aβ. Selected compounds were prepared as O- or N-[(11)C]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-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]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 Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-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 [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ 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 Aβ plaques.

• Authors: Behrooz H Yousefi, André Manook, Alexander Drzezga, Boris von Reutern, Markus Schwaiger, Hans-Jürgen Wester, Gjermund Henriksen
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 4 Pg. 949-56 (Feb 24 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21275403 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Benzothiazoles
• Carbon Radioisotopes
• Radiopharmaceuticals

Topics

• Alzheimer Disease (diagnostic imaging, metabolism)
• Amyloid beta-Peptides (analysis)
• Animals
• Benzothiazoles (chemical synthesis, pharmacokinetics)
• Binding, Competitive
• Carbon Radioisotopes (pharmacokinetics)
• Female
• Humans
• Magnetic Resonance Spectroscopy
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Positron-Emission Tomography (methods)
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacokinetics)
• Tissue Distribution