<br>[18F]-Flortaucipir、[18F]-MK-6240 和 [18F]-PI-2620 死后结合在神经退行性疾病谱中的头对头比较,Acta Neuropathologica

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[18F]-Flortaucipir、[18F]-MK-6240 和 [18F]-PI-2620 死后结合在神经退行性疾病谱中的头对头比较
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2024-01-27 , DOI: 10.1007/s00401-023-02672-z
Cinthya Aguero _{1,

2} , Maeva Dhaynaut ₃ , Ana C Amaral _{1,

2} , S-H Moon ₃ , Ramesh Neelamegam ₃ , Margaret Scapellato _{1,

2} , Carlos Carazo-Casas _{1,

2} , Sunny Kumar _{1,

2} , Georges El Fakhri ₃ , Keith Johnson _{2,

3} , Matthew P Frosch _{1,

2,

4} , Marc D Normandin ₃ , Teresa Gómez-Isla _{1,

2}

Affiliation

我们和其他人已经表明，[¹⁸F]-Flortaucipir 是迄今为止最经过验证的 tau PET 示踪剂，在阿尔茨海默病（AD）中与 tau 聚集体具有很强的亲和力，但在非 AD tau 病中对 tau 聚集体的亲和力相对较低，并且表现出与含有神经黑色素和黑色素的细胞以及出血的脱靶结合。随后开发了几种第二代 tau 示踪剂。[¹⁸F]-MK-6240 和 [¹⁸F]-PI-2620 是获得最多关注的两个。我们最近的数据表明，[¹⁸F]-MK-6240 的结合模式与 [¹⁸F]-Flortaucipir 的结合模式非常相似。本研究旨在直接比较人体组织标本中 [¹⁸F]-Flortaucipir、[¹⁸F]-MK-6240 和 [¹⁸F]-PI-2620 的放射自显影结合特性和脱靶谱，以及它们与单胺氧化酶（毛）的潜在结合。在 AD 和非 AD tau 蛋白病、脑淀粉样血管病、突触核蛋白病、反式反应 DNA 结合蛋白 43 （TDP-43）额颞叶变性和对照的相同死后组织材料中研究了三种示踪剂的磷屏和高分辨率放射自显影模式。我们的结果表明，三种示踪剂显示出几乎相同的放射自显影结合谱。它们都与 AD 中的神经原纤维缠结强烈结合，但似乎与非 AD tau 蛋白病中的 tau 聚集体没有显着结合，这表明它们在体内检测非 AD tau 病变的效用有限。它们都不与含有 β-淀粉样蛋白、α-突触核蛋白或 TDP-43 的病变结合，但它们都显示出与神经黑色素和含黑色素细胞的强烈脱靶结合，以及与出血区域的结合较弱。三种示踪剂的放射自显影结合信号仅被竞争浓度的选择性毛-B 抑制剂 deprenyl 微弱取代，而不是被毛-A 抑制剂克洛吉林取代，这表明毛酶似乎不是它们中的任何一个的重要结合靶标。这些发现为正确解释这三种 tau PET 示踪剂的体内行为提供了相关见解。

"点击查看英文标题和摘要"

Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases

We and others have shown that [¹⁸F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [¹⁸F]-MK-6240 and [¹⁸F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [¹⁸F]-MK-6240 closely parallels that of [¹⁸F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [¹⁸F]-Flortaucipir, [¹⁸F]-MK-6240 and [¹⁸F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers.

更新日期：2024-01-27

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