- Synthesis and evaluation of 11C-labeled imidazo[2,1-b] benzothiazoles (IBTs) as PET tracers for imaging β-amyloid plaques in Alzheimer's disease
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We report a novel series of 11C-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-[11C]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-[11C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([11C]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 Aβ1-40 (Ki = 3.5 nM) and Aβ1-42 (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 [11C]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 [11C]5 and [ 3H]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.
- Yousefi, Behrooz H.,Manook, André,Drzezga, Alexander,Reutern, Boris V.,Schwaiger, Markus,Wester, Hans-Jürgen,Henriksen, Gjermund
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p. 949 - 956
(2011/04/24)
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- SOLID FORMS COMPRISING N-(5-TERT-BUTYL-ISOXAZOL-3-YL)-N'-{4-[7-(2-MORPHOLIN-4-YL-ETHOXY)IMIDAZO[2,1-B][1,3]BENZOTHIAZOL-2-YL]PHENYL}UREA, COMPOSITIONS THEREOF, AND USES THEREWITH
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Solid forms comprising N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin- 4-yl-ethoxy)imidazo[2,l-b][l,3]benzothiazol-2-yl]phenyl}urea, compositions comprising the solid forms, methods of making the solid forms and methods of their use for the treatmen
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Page/Page column 86
(2009/04/25)
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- Identification of N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2- morpholin-4-yl-ethoxy)imidazo-[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor
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Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharma
- Chao, Qi,Sprankle, Kelly G.,Grotzfeld, Robert M.,Lai, Andiliy G.,Carter, Todd A.,Velasco, Anne Marie,Gunawardane, Ruwanthi N.,Cramer, Merryl D.,Gardner, Michael F.,James, Joyce,Zarrinkar, Patrick P.,Patel, Hitesh K.,Bhagwat, Shripad S.
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supporting information; experimental part
p. 7808 - 7816
(2010/09/08)
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- Imidazolothiazole compounds for the treatment of disease
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Compounds, compositions and methods are provided for modulating the activity of receptor kinases and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by receptor kinases.
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Page/Page column 41
(2008/06/13)
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