Synthesis of methoxy-X04 derivatives and their evaluation in Alzheimer's disease pathology.

ABSTRACT

BACKGROUND: Alzheimer's disease is characterized by two notorious protein aggregates in the brain extracellular senile plaques mainly consisting of amyloid-ß peptides and tau-protein-derived intracellular paired helical filaments. The diagnosis of Alzheimer's disease is impaired by insufficient sensitivity and specificity of diagnostic methods to visualize these pathological hallmarks over all disease stages. OBJECTIVE: The established fluorescence marker methoxy-X04 stains plaques, tau tangles and amyloid-derived angiopathies with good specificity, yet it is limited by slow elimination in vivo. Since the need for new markers is high, we prepared methoxy-X04 derivatives and evaluated their potential as imaging agents in Alzheimer's disease pathology. METHODS AND RESULTS: In this study, we describe an improved synthesis for methoxy-X04 and its derivatives and their affinity determination for the respective protein targets by immunohistology and a displacement assay. CONCLUSION: This resulted in the identification of new derivatives of methoxy-X04 with improved binding affinity.