Development of radioiodinated acridine derivatives for in vivo imaging of prion deposits in the brain

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Masao Kawasaki, Takeshi Fuchigami, Nobuya Kobashi, Takehiro Nakagaki, Kazunori Sano, Ryuichiro Atarashi, Sakura Yoshida, Mamoru Haratake, Noriyuki Nishida, Morio Nakayama
Prion diseases are caused by deposition of abnormal prion protein aggregates (PrP^Sc) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrP^Sc 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.

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