. Evaluation of inositol and benzothiazole derivatives for amyloid-β peptide inhibition and amyloid imaging. Human Amyloid Imaging 2010 Meeting Abstracts. 2010 April 9;

Abstract:

Despite numerous recent advances, Alzheimer’s disease continues to pose a challenge both for diagnostic and treatment strategies. We have recently evaluated two compounds for potential use both as amyloid imaging agents and as therapeutic agents.

Multiple lines of evidence suggest that the accumulation of neurotoxic oligomeric aggregates of amyloidbeta (Aβ) may be a central event in the pathogenesis of Alzheimer's disease. It is possible that inhibitors of Aβ aggregation and toxicity may be effective in blocking this pathogenic cascade. Here, we report the development of a compound that could have both diagnostic and therapeutic roles by binding to oligomers. In an effort to combine bioavailability and dual function we have tethered scyllo-inositol, known to bind and neutralize oligomers into soluble complexes, to 2-ethyl-8-methyl-2,8-diazospiro-4,5-decan-1,3-dione, a muscarinic receptor agonist which improves neurotransmitter function. These derivatives have recently been evaluated for Aβ peptide polymerization inhibition.

In addition, F-18 labeled N-2-[fluoropropyl]-2-(4’-(methylamino)phenyl)-6-hydroxybenzothiazole (FMHT) was prepared as a potential imaging agent for Alzheimer’s disease. Brain activity for F-18MHT was pronounced within 2 minutes (4%ID/g) and washed out quickly; brain activity was 1.2%ID/g at 45 minutes and right and left hemispheres were clearly visualized. Initial brain uptake of F-18MHT was higher than that of PIB. Interestingly, in vitro Aβ studies showed cold FMHT had a 25-fold inhibition of Ab polymerization, suggesting that FMHT could be a promising candidate for Alzheimer’s treatment.

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  1. Toronto: HAI Amyloid Imaging Conference Abstracts