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 Sc ) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrP Sc . 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 Sc 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 Sc . The BFC derivatives exhibited high binding affinities (equilibrium dissociation constant [ K d ] = 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 Sc in mBSE-infected mouse brains. Among the BFC derivatives, [ 125 I]BFC-OMe and [ 125 I]BFC-NH 2 exhibited high brain uptake and favorable washout from the mouse brain. In vitro autoradiography demonstrated that the distribution of [ 125 I]BFC-OMe in the brain tissues of mBSE-infected mice was colocalized with PrP Sc deposits. Taken together, BFC derivatives appear to be promising prion imaging probes.