Synthesis and Biological Evaluation of Novel 2-(Benzofuran-2-yl)-chromone Derivatives for In Vivo Imaging of Prion Deposits in the Brain
Synthesis and Biological Evaluation of Novel 2-(Benzofuran-2-yl)-chromone Derivatives for In Vivo Imaging of Prion Deposits in the Brain
复制标题
用于大脑中朊病毒沉积物体内成像的新型 2-(苯并呋喃-2-基)-色酮衍生物的合成和生物学评价
DOI：
10.1021/acsinfecdis.2c00142
复制
发表时间：
2022
影响因子：
5.3
通讯作者：
Fuchigami Takeshi
中科院分区：
文献类型：
--
作者：
Nakaie Mari;Katayama Fumihiro;Nakagaki Takehiro;Yoshida Sakura;Kawasaki Masao;Nishi Kodai;Ogawa Kazuma;Toriba Akira;Nishida Noriyuki;Nakayama Morio;Fuchigami Takeshi
朊病毒病是由瘙痒病朊病毒蛋白聚集体 (PrPSc) 在大脑中沉积引起的致命性神经退行性疾病。我们之前报道过苯乙烯色酮 (SC) 和苯并呋喃 (BF) 衍生物具有作为 PrPSc 成像探针的潜力。为了进一步改善其性能，我们设计并合成了与 SC 和 BF 主链杂交的 2-(苯并呋喃-2-基)-色酮 (BFC) 衍生物，作为新型单光子发射计算机断层扫描探针，用于检测脑 PrPSc 沉积物。使用重组小鼠朊病毒蛋白 (rMoPrP) 聚集体和小鼠适应牛海绵状脑病 (mBSE) 感染小鼠来评估 BFC 衍生物与 PrPSc 的结合特性。 BFC 衍生物对 rMoPrP 聚集体表现出高结合亲和力（平衡解离常数 [Kd] = 22.6–47.7 nM）。所有 BFC 衍生物都对β-淀粉样蛋白聚集体表现出显着的选择性。荧光显微镜证实，BFC 衍生物的荧光信号与 PrPScin mBSE 感染的小鼠大脑中的抗体阳性沉积物相对应。在 BFC 衍生物中，[125I]BFC-OMe 和 [125I]BFC-NH2 表现出较高的脑摄取率和良好的小鼠脑清除率。体外放射自显影表明，[125I]BFC-OMe 在 mBSE 感染小鼠脑组织中的分布与 PrPSc 沉积物共定位。总而言之，BFC 衍生物似乎是有前途的朊病毒成像探针。
Prion diseases are fatal neurodegenerative disorders caused by the deposition of scrapie prion protein aggregates (PrPSc) in the brain. We previously reported that styrylchromone (SC) and benzofuran (BF) derivatives have potential as imaging probes for PrPSc. To further improve their properties, we designed and synthesized 2-(benzofuran-2-yl)-chromone (BFC) derivatives hybridized with SC and BF backbones as novel single-photon emission computed tomography probes for the detection of cerebral PrPScdeposits. Recombinant mouse prion protein (rMoPrP) aggregates and mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice were used to evaluate the binding properties of BFC derivatives to PrPSc. The BFC derivatives exhibited high binding affinities (equilibrium dissociation constant [Kd] = 22.6–47.7 nM) for rMoPrP aggregates. All BFC derivatives showed remarkable selectivity against amyloid beta aggregates. Fluorescence microscopy confirmed that the fluorescence signals of the BFC derivatives corresponded to the antibody-positive deposits of PrPScin mBSE-infected mouse brains. Among the BFC derivatives, [125I]BFC–OMe and [125I]BFC–NH2exhibited high brain uptake and favorable washout from the mouse brain. In vitro autoradiography demonstrated that the distribution of [125I]BFC–OMe in the brain tissues of mBSE-infected mice was colocalized with PrPScdeposits. Taken together, BFC derivatives appear to be promising prion imaging probes.