Patent Watch

May 19, 2014

Detect Alzheimer’s disease plaques with these imaging agents. According to Alzheimer’s Disease International, there are almost 36 million Alzheimer’s disease (AD) patients worldwide. As the global population ages, the number of patients affected by this progressive neurodegenerative disease is expected to increase substantially. Clinical manifestations of AD include cognitive decline, disorientation, language impairment, and permanent memory loss. In the final stages of AD, patients are usually completely dependent on custodial care and are severely cognitively impaired.

The root cause of AD has not been determined, but post mortem studies of AD patients’ brains have revealed the presence of many plaques composed of β-amyloid peptides and neurofibrillary tangles that consist of hyperphosphorylated τ protein filaments. Under normal circumstances, the τ protein is expressed in neurons and plays an important role in forming the neuronal microtubule network. Much like the formation of β-amyloid plaques, the mechanism that causes τ hyperphosphorylation, aggregation, and subsequent plaque formation is unknown.

Some researchers suggest that it may be possible to track AD progression by monitoring plaque formation in patients. If it can be demonstrated that the plaques appear in asymptomatic patients, it may also be possible to identify at-risk patients before the onset of symptoms. Currently, however, the only method for detecting τ aggregates requires histological analysis of biopsy or autopsy samples.

Inventors L. Gabbi, H. Knust, and A. Koblet describe imidazo[2,1]thiazol-3-one derivatives that may be useful in vivo imaging agents for detecting τ and β-amyloid (A-β) plaques in patients. The compounds of the invention have general structure 1 shown in the figure.

Potential in vivo imaging agents for τ and A-β plaques

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The inventors used the thiazine red R displacement fluorescence assay to evaluate the compounds. Several, including the ones listed in the box, had IC50 values below 10 nM for A-β plaques and below 100 nM for τ plaques. 

Derivatives of structure 1 with low IC50 values
Ar R
4-Pyridyl OMe
4-Chlorophenyl OMe
4-Chlorophenyl Cl
4-Chlorophenyl Br
4-Chlorophenyl OH
3-Methyl-4-pyridyl OMe
3-Chlorophenyl OMe

The IC50 is the concentration of the imaging agent at which 50% of plaques are detected by the assay. Low values mean that small amounts of the imaging agent are needed to detect plaques. (Hoffmann-La Roche. WIPO Publication 2014026881, Feb.20, 2014; Benjamin Blass)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.