Preclinical Imaging, Department of Radiological Sciences, University of California, Irvine, CA, USA.
Synapse. 2021 Jan;75(1):e22183. doi: 10.1002/syn.22183. Epub 2020 Aug 6.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6-[ I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline ([ I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN).
Radiosynthesis of [ I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK-6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [ H]PIB for Aβ plaques and [ I]IPPI for Tau in AD and CN brains and evaluate drug effects.
[ I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (-7.8, -8.1, -8.2, -7.5 Kcal/mol) at the four sites were comparable to MK-6240 (-8.7, -8.5, -8.3, -7.5 Kcal/mol). Ratio of average grey matter (GM) [ I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [ I]IPPI in CN was 1.21. Binding of [ I]IPPI correlated with the presence of Tau, confirmed by anti-Tau Dako A0024. Specifically bound [ I]IPPI to Tau in AD brains was displaced by MK-6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [ I]IPPI binding at >1 µM concentrations.
[ I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是 Tau 蛋白聚集形成成对的螺旋丝，导致大脑中的神经原纤维缠结（NFT）。本研究的目的是开发和评估一种新型放射性碘标记示踪剂 6-[I]碘-3-（1H-吡咯并[2,3-c]吡啶-1-基）异喹啉（[I]IPPI），用于与 Tau 蛋白（Ki=0.75 nM）结合的有效性，该蛋白来自死后的人脑（AD 和认知正常（CN）。
通过放射性碘去锡和色谱纯化进行[I]IPPI 的放射合成。评估 IPPI 和 MK-6240 与 Tau 纤维结合的计算建模研究。进行体外放射性自显影研究，用[H]PIB 检测 Aβ 斑块，用[I]IPPI 检测 AD 和 CN 脑中的 Tau，并评估药物作用。
[I]IPPI 以> 95%的纯度生产。IPPI 的分子建模显示，IPPI（-7.8、-8.1、-8.2、-7.5 Kcal/mol）在四个部位的结合能与 MK-6240（-8.7、-8.5、-8.3、-7.5 Kcal/mol）相当。AD 中 AD 与 CN 相比，平均灰质（GM）[I]IPPI 的比值为 7.31（p=0.07），AD GM/白质（WM）= 4.35（p=0.09）。CN 中平均 GM/WM [I]IPPI 的比值为 1.21。[I]IPPI 的结合与 Tau 的存在相关，这一点被 Tau 的抗 Dako A0024 抗体所证实。AD 大脑中特异性结合的[I]IPPI 可被 MK-6240 和 IPPI（>90%）置换。单胺氧化酶抑制剂（MAO）抑制剂 deprenyl 和 clorgyline 在>1 µM 浓度下对[I]IPPI 结合产生影响。
[I]IPPI 在人类 AD 额叶皮层和前扣带回中表现出高结合性，是 Tau 成像的合适放射性碘标记配体。
