Synthesis and Biological Evaluation of Novel 2-(Benzofuran-2-yl)-chromone Derivatives for In Vivo Imaging of Prion Deposits in the Brain.

Prion diseases are fatal neurodegenerative disorders caused by the deposition of scrapie prion protein aggregates (PrP) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrP. To further improve their properties, we designed and synthesized 2-(benzofuran-2-yl)-chromone (BFC) derivatives hybridized with SC and BF backbones as novel single-photon emission computed tomography probes for the detection of cerebral PrP deposits. Recombinant mouse prion protein (rMoPrP) aggregates and mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice were used to evaluate the binding properties of BFC derivatives to PrP. The BFC derivatives exhibited high binding affinities (equilibrium dissociation constant [] = 22.6-47.7 nM) for rMoPrP aggregates. All BFC derivatives showed remarkable selectivity against amyloid beta aggregates. Fluorescence microscopy confirmed that the fluorescence signals of the BFC derivatives corresponded to the antibody-positive deposits of PrP in mBSE-infected mouse brains. Among the BFC derivatives, [I]BFC-OMe and [I]BFC-NH exhibited high brain uptake and favorable washout from the mouse brain. In vitro autoradiography demonstrated that the distribution of [I]BFC-OMe in the brain tissues of mBSE-infected mice was colocalized with PrP deposits. Taken together, BFC derivatives appear to be promising prion imaging probes.