Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue
Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue
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DOI：
10.1186/s40478-019-0686-6
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发表时间：
2019-03-11
影响因子：
7.1
通讯作者：
Gomez-Isla, Teresa
中科院分区：
文献类型：
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作者：
Aguero, Cinthya;Dhaynaut, Maeva;Gomez-Isla, Teresa
[F-18]-MK-6240是一种新型的tau正电子发射断层扫描（PET）示踪剂，最近被发现用于体内检测神经原纤维缠结，有可能提高阿尔茨海默病的诊断准确性。我们已经研究了区域和底物特异性结合模式，以及该示踪剂在人脑组织上可能的脱靶结合，以推进其有效性。我们应用[F-18]-MK-6240荧光屏和高分辨率放射自显影技术对病理诊断为阿尔茨海默病、额颞叶变性-tau（皮克病、进行性核上性麻痹和皮质基底变性）、慢性外伤性脑病、额颞叶变性- tar dna结合蛋白43 （TDP-43）、路易体痴呆、脑淀粉样血管病和老年对照无病理改变的神经退行性疾病。我们还直接比较了[F-18]-MK-6240和[F-18]-AV-1451在人体组织中的结合特性，并在选择性单胺氧化酶A （MAO-A）和单胺氧化酶B （MAO-B）抑制剂存在的情况下，使用放射自显影技术检测了这两种tau示踪剂与单胺氧化酶（MAO）的潜在非特异性结合。我们的数据表明，MK-6240在阿尔茨海默病中与神经原纤维缠结紧密结合，但在非阿尔茨海默病中与tau蛋白聚集体的结合似乎并不明显，这表明它在体内检测这些病理方面可能具有有限的效用。没有证据表明与含有-淀粉样蛋白，-synuclein或TDP-43的病变结合。此外，我们发现MK-6240与神经黑色素和含黑色素细胞有很强的脱靶结合，与出血区域的结合较弱。这些结合模式几乎与我们小组和其他人之前报道的[F-18]-AV-1451的结合模式相同。值得注意的是，[F-18]-MK-6240和[F-18]-AV-1451的放射自显影结合信号仅被选择性MAO- b抑制剂去戊烯基的竞争浓度所取代，而不被MAO- a抑制剂clorgyline所取代，这表明MAO酶似乎不是这两种示踪剂中任何一种的重要结合靶标。总之，这些新发现为正确解释体内[F-18]-MK-6240 PET成像提供了相关的见解。
[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick's disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease. We also directly compared the binding properties of [F-18]-MK-6240 and [F-18]-AV-1451 in human tissue, and examined potential nonspecific binding of both tau tracers to monoamine oxidases (MAO) by using autoradiography in the presence of selective monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) inhibitors. Our data indicate that MK-6240 strongly binds to neurofibrillary tangles in Alzheimer disease but does not seem to bind to a significant extent to tau aggregates in non-Alzheimer tauopathies, suggesting that it may have a limited utility for the in vivo detection of these pathologies. There is no evidence of binding to lesions containing -amyloid, -synuclein or TDP-43. In addition, we identified MK-6240 strong off-target binding to neuromelanin and melanin-containing cells, and some weaker binding to areas of hemorrhage. These binding patterns are nearly identical to those previously reported by our group and others for [F-18]-AV-1451. Of note, [F-18]-MK-6240 and [F-18]-AV-1451 autoradiographic binding signals were 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 these two tracers. Together these novel findings provide relevant insights for the correct interpretation of in vivo [F-18]-MK-6240 PET imaging.