Abstract
Prion diseases are fatal neurodegenerative diseases characterised by deposition of amyloid plaques containing abnormal prion protein aggregates (PrPSc). This study aimed to evaluate the potential of radioiodinated flavonoid derivatives for single photon emission computed tomography (SPECT) imaging of PrPSc. In vitro binding assays using recombinant mouse PrP (rMoPrP) aggregates revealed that the 4-dimethylamino-substituted styrylchromone derivative (SC-NMe2) had higher in vitro binding affinity (Kd = 24.5 nM) and capacity (Bmax = 36.3 pmol/nmol protein) than three other flavonoid derivatives (flavone, chalcone, and aurone). Fluorescent imaging using brain sections from mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice demonstrated that SC-NMe2 clearly labelled PrPSc-positive prion deposits in the mice brain. Two methoxy SC derivatives, SC-OMe and SC-(OMe)2, also showed high binding affinity for rMoPrP aggregates with Ki values of 20.8 and 26.6 nM, respectively. In vitro fluorescence and autoradiography experiments demonstrated high accumulation of [125I]SC-OMe and [125I]SC-(OMe)2 in prion deposit-rich regions of the mBSE-infected mouse brain. SPECT/computed tomography (CT) imaging and ex vivo autoradiography demonstrated that [123I]SC-OMe showed consistent brain distribution with the presence of PrPSc deposits in the mBSE-infected mice brain. In conclusion, [123I]SC-OMe appears a promising SPECT radioligand for monitoring prion deposit levels in the living brain.
Highlights
(OMe)[2], showed high binding affinity for recombinant mouse PrP (rMoPrP) aggregates with Ki values of 20.8 and 26.6 nM, respectively
To evaluate the binding properties of flavonoid derivatives for PrPSc in brain tissue, the mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice were prepared as a mouse model of prion diseases[25,26]
Okamura et al reported on the consistent in vitro autoradiograms of [18F]BF-227 with PrP deposits in GSS brain sections
Summary
(OMe)[2], showed high binding affinity for rMoPrP aggregates with Ki values of 20.8 and 26.6 nM, respectively. We have developed radiolabelled flavonoid-related compounds, such as flavones (FLs)[17,18], chalcones (CLs)[19,20], aurones (ARs)[21,22], and styrylchromones (SCs)[23,24], as potential SPECT or PET imaging agents for Aβ plaques (Fig. 1) We considered that these flavonoid derivatives have potential as diagnostic agents for prion diseases. We aimed to explore the feasibility of the flavonoid derivatives as imaging probes for detecting PrPSc in the living brain via in vitro experiments using recombinant mouse PrP protein (rMoPrP) and brain slices from mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice as prion disease models, followed by SPECT/CT studies in the mBSE-infected mice. We discovered that SPECT/CT imaging with a methoxy SC derivative [123I]SC-OMe successfully visualised the PrPSc–positive regions in the brain of the prion disease mouse model
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