Kawasaki Masao, Fuchigami Takeshi, Kobashi Nobuya, Nakagaki Takehiro, Sano Kazunori, Atarashi Ryuichiro, Yoshida Sakura, Haratake Mamoru, Nishida Noriyuki, Nakayama Morio
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Bioorg Med Chem. 2017 Feb 1;25(3):1085-1093. doi: 10.1016/j.bmc.2016.12.020. Epub 2016 Dec 19.
Prion diseases are caused by deposition of abnormal prion protein aggregates (PrP) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrP 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 [I]2 exhibited the highest binding affinity for rMoPrP aggregates with an equilibrium dissociation constant (K) 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.
朊病毒疾病是由异常朊病毒蛋白聚集体（PrP）在中枢神经系统中的沉积引起的。本研究旨在开发能够检测脑内PrP沉积物的体内成像探针。我们合成了几种具有2,9-取代基的基于喹吖因的吖啶（AC）衍生物并对其进行放射性碘化。使用重组小鼠朊病毒蛋白（rMoPrP）聚集体和适应小鼠的牛海绵状脑病（mBSE）感染小鼠的脑切片，对AC衍生物作为朊病毒成像探针进行评估。还评估了这些化合物在小鼠体内的分布。2-甲氧基衍生物[I]2对rMoPrP聚集体表现出最高的结合亲和力，平衡解离常数（K）值为43.4nM。用2进行荧光成像显示，在mBSE感染小鼠脑内硫黄素T（ThT）阳性淀粉样沉积物处有清晰的信号。尽管在AC衍生物与聚集体的体外结合和这些化合物在脑内的体内分布之间观察到差异，并且在本研究中我们未能鉴定出预期的朊病毒成像探针，但AC衍生物可能被认为是开发体内成像探针的有用支架。对这些AC衍生物进行进一步的化学修饰可能会发现临床上适用的朊病毒成像探针。
