Development of a PET radioligand selective for cerebral amyloid angiopathy.
Development of a PET radioligand selective for cerebral amyloid angiopathy.
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DOI：
10.1016/j.nucmedbio.2020.05.001
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发表时间：
2021-01
影响因子：
3.1
通讯作者：
Ikonomovic MD
中科院分区：
文献类型：
--
作者：
Abrahamson EE;Stehouwer JS;Vazquez AL;Huang GF;Mason NS;Lopresti BJ;Klunk WE;Mathis CA;Ikonomovic MD
使用放射性标记的淀粉样蛋白结合化合物的正电子发射断层扫描 (PET) 通过检测和纵向跟踪活人中的纤维状淀粉样蛋白-β (Aβ) 沉积物，推动了阿尔茨海默病 (AD) 领域的发展。然而，该技术无法区分脑实质中的 Aβ 沉积（淀粉样斑块）和血管中的 Aβ 沉积（脑淀粉样血管病，CAA）。开发能够选择性检测 CAA 的 PET 放射配体将有助于阐明其对全脑淀粉样变性和 AD 临床症状的影响，并有助于表征 AD 患者中抗 Aβ 免疫疗法（如 CAA）的副作用。从淀粉样蛋白结合染料刚果红的一组类似物中合成了候选 CAA 选择性化合物 (1)。测定了化合物 1 与 Aβ 原纤维的结合亲和力和亲脂性，并在转基因 APP/PS1 小鼠和受 AD 病理影响的死后人脑中离体和体内评估了 CAA 与实质斑块沉积物的选择性。化合物 1 显示了 Aβ 结合染料（例如硫代黄素-S）的特征，因为当应用于 Aβ 淀粉样变性转基因 APP/PS1 小鼠模型和 AD 脑的组织学切片时，它可以标记实质 Aβ 斑块和 CAA。因此，化合物 1 缺乏分子选择性来区分 CAA 中的 Aβ 沉积物和斑块中的 Aβ 沉积物。然而，当静脉注射给活体 APP/PS1 小鼠时，在使用体内双光子显微镜以及离体组织学和放射自显影术进行评估时，化合物 1 优先标记 CAA。我们假设化合物 1 对 CAA 的选择性归因于由于羧酸盐部分的高极性性质，其对血脑屏障的渗透有限，从而限制了对实质斑块的进入并促进了血管壁中 Aβ 沉积物的选择性体内标记（即“递送选择性”）。
Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer’s disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-β (Aβ) deposits in living people. However, this technique cannot distinguish between Aβ deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aβ immunotherapies in AD patients, such as CAA. A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aβ fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. Compound 1 displays characteristics of Aβ binding dyes, such as thioflavin-S, in that it labels both parenchymal Aβ plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aβ amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aβ deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aβ deposits in the vascular wall (i.e., “delivery selectivity”).
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影响因子：
6.1
作者：
Klunk, WE;Wang, YM;Mathis, CA
通讯作者：
Mathis, CA
DOI：
10.1097/00005072-199804000-00008
发表时间：
1998-04-01
影响因子：
3.2
作者：
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通讯作者：
Greenberg, SM
影响因子：
9.9
作者：
Knudsen, KA;Rosand, J;Greenberg, SM
通讯作者：
Greenberg, SM
影响因子：
9.9
作者：
Gurol, M. Edip;Dierksen, Gregory;Greenberg, Steven M.
通讯作者：
Greenberg, Steven M.
影响因子：
6.1
作者：
Garcia-Alloza, Monica;Robbins, Elissa M.;Frosch, Matthew P.
通讯作者：
Frosch, Matthew P.