Development of Radioiodinated Benzofuran Derivatives for in Vivo Imaging
of Prion Deposits in the Brain
ABSTRACT
Prion diseases are fatal neurodegenerative disorders associated with the
deposition of abnormal prion protein aggregates (PrPSc) in the brain tissue. Here, we report the development of 125I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed
tomography (SPECT) imaging probes to detect cerebral PrPSc 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, [125I]5-IBF-NHMe displayed the highest adsorption rate and potent binding affinity
with an equilibrium dissociation constant (Kd) of 12.3 nM. Fluorescence imaging using IBF-NHMe showed clear signals
of the PrPSc-positive amyloid deposits in the mBSE-infected mouse brains. Biodistribution
studies in normal mice demonstrated slow uptake and clearance from the
brain of 125I-IBF derivatives. Among the derivatives, [125I]6-IBF-NH2 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 in vivo imaging,
these compounds showed prospective binding properties to PrPSc. Further chemical modification of these IBF derivatives may contribute
to the discovery of clinically applicable prion imaging probes. KEYWORDS:
prion disease, PrPSc, benzofuran, single photon emission computed tomography
(SPECT)