Synthesis of fluorinated curcumin derivatives for detecting amyloid plaques by 19F-MRI

Abstract

The most prominent pathophysiological hallmark of Alzheimer's disease is the aggregation of amyloid-β (Aβ) peptides into senile plaques. Curcumin and its derivatives exhibit a high affinity for binding to Aβ fibrils, effectively inhibiting their growth. This property holds promise for both therapeutic applications and diagnostic molecular imaging. In this study, curcumin was functionalized with perfluoro-tert-butyl groups to create candidate molecular probes specifically targeted to Aβ fibrils for use in ¹⁹F-magnetic resonance imaging. Two types of fluorinated derivatives were considered: mono-substituted (containing nine fluorine atoms per molecule) and disubstituted (containing eighteen fluorine atoms). The linker connecting the perfluoro moiety with the curcumin scaffold was evaluated for its impact on binding affinity and water solubility. All mono-substituted compounds and one disubstituted compound exhibited a binding affinity toward Aβ fibrils on the same order of magnitude as reference curcumin. The insertion of a charged carboxylate group into the linker enhanced the water solubility of the probes. Compound Curc-Glu-F9 (with one L-glutamyl moiety and a perfluoro-tert-butyl group), showed the best properties in terms of binding affinity towards Aβ fibrils, water solubility, and intensity of the ¹⁹F-NMR signal in the Aβ oligomer bound form.