Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.
J Med Chem. 2023 Aug 10;66(15):10628-10638. doi: 10.1021/acs.jmedchem.3c00775. Epub 2023 Jul 24.
A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; ) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [H] provided (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. positron emission tomography (PET) imaging in rats with [F] demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1-indol-2-yl)pyrimidin-2-yl)morpholine; ). Binding assays with [H] provided (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta. PET imaging in rats with [F] demonstrated a higher brain penetration than [F] and rapid clearance from normal brain tissues. We anticipate that and will be useful for the identification of other potent novel 4R-tau radiotracers.
化学指纹搜索鉴定 Z3777013540（1-(5-(6-氟-1-吲哚-2-基)嘧啶-2-基)哌啶-4-醇；）为潜在的 4R-tau 结合配体。在阿尔茨海默病（AD）、进行性核上性麻痹（PSP）和皮质基底节变性（CBD）死后脑组织中进行的 [H]结合测定，AD 的（nM）值为 4.0，PSP 为 5.1，CBD 为 4.5。用 [F]进行大鼠正电子发射断层扫描（PET）成像显示出良好的脑穿透性和从正常脑组织中快速清除。随后使用 作为查询进行分子相似性搜索，发现了另一种有前途的化合物 Z4169252340（4-(5-(6-氟-1-吲哚-2-基)嘧啶-2-基)吗啉；）。用 [H]进行的结合测定，AD 的（nM）值为 1.2，PSP 为 1.6，CBD 为 1.7，对结合聚集的 α-突触核蛋白和淀粉样-β的亲和力较低。用 [F]进行大鼠 PET 成像显示出比 [F]更高的脑穿透性，并从正常脑组织中快速清除。我们预计 和 将有助于鉴定其他有效的新型 4R-tau 放射性示踪剂。
