AC Immune SA, EPFL Innovation Park, Building B, 1015 Lausanne, Switzerland.
Life Molecular Imaging GmbH, Tegeler Strasse 6-7, 13353 Berlin, Germany.
Bioorg Med Chem. 2021 Dec 15;52:116528. doi: 10.1016/j.bmc.2021.116528. Epub 2021 Nov 20.
Tau aggregates represent a critical pathology in Alzheimer's disease (AD) and other forms of dementia. The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD. Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies. To evaluate the impact of the N-atom position with respect to Tau- and off-target binding, tricyclic core analogs of PI-2620 with nitrogen atoms at different positions were prepared. Affinity to aggregated Tau was evaluated using human AD brain homogenates, and their off-target binding was evaluated in a monoamine oxidase A (MAO-A) competition assay. The novel tricyclic core derivatives all displayed inferior Tau binding or MAO-A off-target selectivity, indicating PI-2620 to be the optimal design for high affinity binding to Tau and high MAO-A selectivity.
Tau 聚集物代表了阿尔茨海默病 (AD) 和其他形式痴呆症的关键病理学。在特定脑区的 Tau 神经纤维缠结的程度与 AD 中观察到的认知能力下降程度非常吻合。化合物 1 (PI-2620) 最近被确定为一种有前途的 AD 和非 AD tau 病的 Tau 正电子发射断层扫描示踪剂。为了评估 N-原子位置对 Tau 和非靶点结合的影响，制备了具有不同位置氮原子的 PI-2620 的三环核心类似物。使用人 AD 脑匀浆评估对聚集 Tau 的亲和力，并在单胺氧化酶 A (MAO-A) 竞争测定中评估其非靶点结合。新型三环核心衍生物的 Tau 结合或 MAO-A 非靶点选择性均较差，表明 PI-2620 是高亲和力结合 Tau 和高 MAO-A 选择性的最佳设计。
