Lipophilic analogs of thioflavin S were synthesized and radiolabeled with positron or single photon emitting radionuclides. The binding affinity for Aβ was evaluated using isolated amyloid fibrils from human brain tissue. Binding specificity was assessed using fluorescent tissue staining. In vivo brain uptake was evaluated in mice. Following synthesis, neutral analogs of thioflavin S capable of radiolabeling with 11C or 125I, were found to bind isolated human Aβ with affinities in the nanomolar range. Fluorescent tissue staining showed selective binding to Aβ deposits in vitro. Biodistribution of selected compounds displayed high brain permeability at early time points. At later points, the compounds were cleared from the normal brain, indicating low non-specific binding in vivo. These studies indicated that novel amyloid imaging probes can be developed based on thioflavin S that readily entered the brain and selectively bound to Aβ deposits and neurofibrilary tangles. Potential applications of these amyloid binding agents include facilitating drug screening in animal models and use as in vivo markers of early and definitive diagnosis of AD.
Keywords: Amyloid-β, Alzheimer's disease, Thioflavin S, PET, SPECT, Imaging
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