Development of radioiodinated acridine derivatives for in vivo imaging
of prion deposits in the brain
ABSTRACT
Prion diseases are caused by deposition of abnormal prion protein aggregates (PrPSc) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrPSc
deposits. We synthesized several quinacrine-based acridine (AC)
derivatives with 2,9-substitution and radioiodinated them. The AC
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. The
distribution of these compounds in mice was also evaluated. The
2-methoxy derivative [125I]2 exhibited the highest binding affinity for rMoPrP aggregates with an equilibrium dissociation constant (Kd)
value of 43.4nM. Fluorescence imaging with 2 showed clear signals at
the thioflavin T (ThT)-positive amyloid deposits in the mBSE-infected
mouse brain. Although a discrepancy was observed between the in vitro
binding of AC derivatives to the aggregates and in vivo distribution of
these compounds in the brain and we failed to identify prospective
prion-imaging probes in this study, the AC derivatives may be considered
a useful scaffold for the development of in vivo imaging probes.
Further chemical modification of these AC derivatives may discover
clinically applicable prion imaging probes.