Development of Radioiodinated Benzofuran Derivatives for Imaging of Prion Deposits in the Brain.

Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrP) in the brain tissue. Here, we report the development of I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrP deposits. We synthesized and radioiodinated several 5-IBF and 6-IBF derivatives. The IBF derivatives were evaluated as prion imaging probes using recombinant mouse prion protein (rMoPrP) aggregates and brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. Although all the IBF derivatives were strongly adsorbed on the rMoPrP aggregates, [I]5-IBF-NHMe displayed the highest adsorption rate and potent binding affinity with an equilibrium dissociation constant () of 12.3 nM. Fluorescence imaging using IBF-NHMe showed clear signals of the PrP-positive amyloid deposits in the mBSE-infected mouse brains. Biodistribution studies in normal mice demonstrated slow uptake and clearance from the brain of I-IBF derivatives. Among the derivatives, [I]6-IBF-NH showed the highest peak brain uptake [2.59% injected dose (ID)/g at 10 min] and good clearance (0.51% ID/g at 180 min). Although the brain distribution of IBF derivatives should still be optimized for imaging, these compounds showed prospective binding properties to PrP. Further chemical modification of these IBF derivatives may contribute to the discovery of clinically applicable prion imaging probes.