Development of Radioiodinated Benzofuran Derivatives for in Vivo Imaging of Prion Deposits in the Brain
Development of Radioiodinated Benzofuran Derivatives for in Vivo Imaging of Prion Deposits in the Brain
复制标题
开发放射性碘化苯并呋喃衍生物，用于大脑中朊病毒沉积物的体内成像
DOI：
10.1021/acsinfecdis.8b00184
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发表时间：
2019
影响因子：
5.3
通讯作者：
Nakayama Morio
中科院分区：
文献类型：
--
作者：
Fuchigami Takeshi;Kawasaki Masao;Koyama Ryusuke;Nakaie Mari;Nakagaki Takehiro;Sano Kazunori;Atarashi Ryuichiro;Yoshida Sakura;Haratake Mamoru;Ono Masahiro;Nishida Noriyuki;Nakayama Morio
朊病毒病是与异常朊病毒蛋白聚集体（PrPSc）在脑组织中沉积相关的致命性神经退行性疾病。在这里，我们报告的发展125碘标记的碘苯并呋喃（IBF）衍生物作为单光子发射计算机断层扫描（SPECT）成像探针检测脑PrPSc存款。我们合成了几种5-IBF和6-IBF衍生物并进行了放射性碘标记。使用重组小鼠朊蛋白（rMoPrP）聚集体和小鼠适应性牛海绵状脑病（mBSE）感染小鼠的脑切片，评价IBF衍生物作为朊蛋白成像探针。虽然所有的IBF衍生物强烈吸附在rMoPrP聚集体上，[125 I]5-IBF-NHMe显示最高的吸附速率和有效的结合亲和力，平衡解离常数（Kd）为12.3 nM。使用IBF-NHMe的荧光成像显示在mBSE感染的小鼠脑中PrPSc阳性淀粉样蛋白沉积物的清晰信号。在正常小鼠体内的生物分布研究表明，125 I-IBF衍生物的脑摄取和清除缓慢。在这些衍生物中，[125 I]6-IBF-NH 2显示出最高的脑摄取峰值[10 min时2.59%注射剂量（ID）/g]和良好的清除率（180 min时0.51% ID/g）。尽管IBF衍生物的脑分布仍需优化以用于体内成像，但这些化合物显示出与PrPSc的前瞻性结合特性。这些IBF衍生物的进一步化学修饰可能有助于发现临床上可应用的朊病毒成像探针。
Prion diseases are fatal neurodegenerative disorders associated with the deposition of abnormal prion protein aggregates (PrPSc) in the brain tissue. Here, we report the development of125I-labeled iodobenzofuran (IBF) derivatives as single photon emission computed tomography (SPECT) imaging probes to detect cerebral PrPScdeposits. 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, [125I]5-IBF-NHMe displayed the highest adsorption rate and potent binding affinity with an equilibrium dissociation constant (Kd) of 12.3 nM. Fluorescence imaging using IBF-NHMe showed clear signals of the PrPSc-positive amyloid deposits in the mBSE-infected mouse brains. Biodistribution studies in normal mice demonstrated slow uptake and clearance from the brain of125I-IBF derivatives. Among the derivatives, [125I]6-IBF-NH2showed 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 forin vivoimaging, these compounds showed prospective binding properties to PrPSc. Further chemical modification of these IBF derivatives may contribute to the discovery of clinically applicable prion imaging probes.