Fuchigami Takeshi, Kawasaki Masao, Koyama Ryusuke, Nakaie Mari, Nakagaki Takehiro, Sano Kazunori, Atarashi Ryuichiro, Yoshida Sakura, Haratake Mamoru, Ono Masahiro, 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 Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences , Nagasaki University , 1-12-4 Sakamoto , Nagasaki 852-8523 , Japan.
ACS Infect Dis. 2019 Dec 13;5(12):2003-2013. doi: 10.1021/acsinfecdis.8b00184. Epub 2019 Mar 27.
Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrP) in the brain tissue. Here, we report the development of I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrP 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, [I]5-IBF-NHMe displayed the highest adsorption rate and potent binding affinity with an equilibrium dissociation constant () of 12.3 nM. Fluorescence imaging using IBF-NHMe showed clear signals of the PrP-positive amyloid deposits in the mBSE-infected mouse brains. Biodistribution studies in normal mice demonstrated slow uptake and clearance from the brain of I-IBF derivatives. Among the derivatives, [I]6-IBF-NH 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 imaging, these compounds showed prospective binding properties to PrP. Further chemical modification of these IBF derivatives may contribute to the discovery of clinically applicable prion imaging probes.
朊病毒病是与异常朊病毒蛋白聚集体（PrP）在脑组织中沉积相关的致命性神经退行性疾病。在此，我们报告了作为单光子发射计算机断层扫描（SPECT）成像探针的I标记碘苯并呋喃（IBF）衍生物的研发，用于检测脑内PrP沉积物。我们合成并对几种5-IBF和6-IBF衍生物进行了放射性碘化。使用重组小鼠朊病毒蛋白（rMoPrP）聚集体和小鼠适应型牛海绵状脑病（mBSE）感染小鼠的脑切片，对IBF衍生物作为朊病毒成像探针进行了评估。尽管所有IBF衍生物都强烈吸附在rMoPrP聚集体上，但[I]5-IBF-NHMe显示出最高的吸附率和强大的结合亲和力，平衡解离常数（）为12.3 nM。使用IBF-NHMe的荧光成像显示mBSE感染小鼠脑中PrP阳性淀粉样沉积物有清晰信号。正常小鼠的生物分布研究表明I-IBF衍生物从脑中摄取和清除缓慢。在这些衍生物中，[I]6-IBF-NH显示出最高的脑摄取峰值[10分钟时为2.59%注射剂量（ID）/克]和良好的清除率（180分钟时为0.51% ID/克）。尽管IBF衍生物的脑分布仍需针对成像进行优化，但这些化合物对PrP显示出有前景的结合特性。对这些IBF衍生物进行进一步的化学修饰可能有助于发现临床适用的朊病毒成像探针。
