Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site
Characterization of the binding of tau imaging ligands to melanin-containing cells: putative off-target-binding site
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tau 成像配体与含黑色素细胞的结合特征：推定的脱靶结合位点
DOI：
10.1007/s12149-019-01344-x
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发表时间：
2019
影响因子：
2.6
通讯作者：
Ishii Kenji
中科院分区：
文献类型：
--
作者：
Tago Tetsuro;Toyohara Jun;Harada Ryuichi;Furumoto Shozo;Okamura Nubuyuki;Kudo Yukitsuka;Takahashi-Fujigasaki Junko;Murayama Shigeo;Ishii Kenji
β淀粉样蛋白斑块和由tau蛋白组成的神经元缠结是阿尔茨海默病的神经病理学标志。近年来，使用tau配体进行正电子发射断层扫描（PET）在阿尔茨海默病研究中取得了显著进展。然而，脱靶结合的问题，即配体与没有tau病变的区域的结合，仍然没有解决。具有含黑色素细胞（MCC）的组织已被建议作为tau配体的结合靶标。在本研究中，我们的特点是MCC的结合特性的代表性tau PET ligandsMethodsAutoradiographic研究[18 F]AV-1451和[18 F] THK 5351进行尸检人中脑部分。用B16 F10黑色素瘤细胞进行[18 F]AV-1451和[18 F] THK 5351的饱和结合试验。25个化合物对[18 F] THK 5351结合B16 F10细胞的阻断作用被用来研究化学结构和MCC binding.ResultsAutoradiography之间的关系，证明在黑质的放射性配体的特异性结合。[18 F]AV-1451和[18 F] THK 5351与黑素瘤细胞表现出可饱和结合（[18 F]AV-1451：Kd= 669 ± 196 nM，Bmax= 622 ± 269 pmol/mg蛋白; [18 F] THK 5351：Kd= 441 ± 126 nM，Bmax= 559 ± 75.5 pmol/mg蛋白）。在黑色素瘤细胞的阻断研究中，携带多个芳环和氨基吡啶基团的化合物，包括tau配体如AV-1451、PBB 3和MK-6240的先导化合物，表现出与THK 5351自阻断相当的[18F] THK 5351结合抑制结论这些研究表明，[18 F]AV-1451和[18 F] THK 5351的结合特性足以预期突出具有高密度MCC的组织。本研究的结果应有助于开发不与MCC结合的神经影像配体。
ObjectiveAmyloid-β plaques and neurofibrillary tangles composed of tau protein are the neuropathological hallmarks of Alzheimer’s disease. In recent years, marked progress has been made in Alzheimer’s disease research using tau ligands for positron emission tomography (PET). However, the issue of off-target binding, that is, the binding of ligands to regions without tau pathology, remains unresolved. Tissues with melanin-containing cells (MCCs) have been suggested as binding targets for tau ligands. In the present study, we characterized the MCC-binding properties of representative tau PET ligands.MethodsAutoradiographic studies of [18F]AV-1451 and [18F]THK5351 were conducted using postmortem human midbrain sections. Saturation-binding assays of [18F]AV-1451 and [18F]THK5351 were performed with B16F10 melanoma cells. The blocking effects of 25 compounds against [18F]THK5351 binding to B16F10 cells were used to investigate the relationship between chemical structure and MCC binding.ResultsAutoradiography demonstrated specific binding of the radioligands in the substantia nigra. [18F]AV-1451 and [18F]THK5351 exhibited saturable binding to melanoma cells ([18F]AV-1451:Kd= 669 ± 196 nM,Bmax= 622 ± 269 pmol/mg protein; [18F]THK5351:Kd= 441 ± 126 nM,Bmax= 559 ± 75.5 pmol/mg protein). In blocking studies with melanoma cells, compounds bearing multiple aromatic rings and an aminopyridine group, including tau ligands such as AV-1451, PBB3, and a lead compound of MK-6240, exhibited the inhibition of [18F]THK5351 binding comparable to self-blocking by THK5351 (> 70% at 10 µM).ConclusionsThese studies suggest that the binding properties of [18F]AV-1451 and [18F]THK5351 are sufficient to expect highlighting of tissues with a high density of MCCs. The findings of the present study should aid the development of neuroimaging ligands that do not bind to MCC.
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黑质神经黑色素：结构、合成和分子行为
DOI：
10.1136/mp.54.6.414
发表时间：
2001
期刊：
Molecular Pathology
影响因子：
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作者：
L. Zecca;D. Tampellini;M. Gerlach;P. Riederer;R. Fariello;D. Sulzer
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发表时间：
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The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
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作者：
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V. Villemagne
影响因子：
4.7
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Double, KL;Zecca, L;Gerlach, M
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DOI：
10.1038/s41531-017-0023-3
发表时间：
2017
期刊：
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影响因子：
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作者：
Coakeley S;Strafella AP
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影响因子：
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作者：
Uematsu M;Nakamura A;Ebashi M;Hirokawa K;Takahashi R;Uchihara T
通讯作者：
Uchihara T