Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Geriatric Research Education and Clinical Center, VA Pittsburgh HS, Pittsburgh, PA, USA.
Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA.
Nucl Med Biol. 2021 Jan;92:85-96. doi: 10.1016/j.nucmedbio.2020.05.001. Epub 2020 May 12.
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").
正电子发射断层扫描（PET）使用放射性标记的淀粉样蛋白结合化合物，通过在活体中检测和纵向追踪纤维状淀粉样蛋白-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（淀粉样斑块）和血管中的 Aβ 沉积物（脑淀粉样血管病，CAA）。开发一种能够选择性检测 CAA 的 PET 放射性配体将有助于阐明其对 AD 患者大脑淀粉样变性和临床症状的贡献，并有助于描述 AD 患者抗 Aβ 免疫疗法的副作用，如 CAA。
从一组淀粉样蛋白结合染料刚果红类似物中合成了一种候选 CAA 选择性化合物（1）。测定了化合物 1 与 Aβ 纤维的结合亲和力和脂溶性，并评估了其在 APP/PS1 转基因小鼠体内和 AD 患者死后大脑中对 CAA 与实质斑块沉积的选择性。
化合物 1 具有 Aβ 结合染料，如硫黄素-S 的特性，当应用于来自 APP/PS1 转基因 Aβ 淀粉样变性和 AD 大脑的组织学切片时，它标记了实质 Aβ 斑块和 CAA。因此，化合物 1 缺乏分子选择性，无法区分 CAA 中的 Aβ 沉积与斑块中的 Aβ 沉积。然而，当静脉内给予活的 APP/PS1 小鼠时，当使用体内双光子显微镜和离体组织学和放射自显影术评估时，化合物 1 优先标记 CAA。
我们假设化合物 1 对 CAA 的选择性归因于其羧基部分的高度极性，导致其穿透血脑屏障的能力有限，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“传递选择性”）。
