Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada.
Department of Psychiatry, University of Toronto, Toronto, Canada.
Nat Commun. 2024 Jun 14;15(1):5109. doi: 10.1038/s41467-024-49258-1.
Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [F]OXD-2115, using ligand-based design. Over 150 analogues of OXD-2115 were synthesized and screened in post-mortem brain tissue for tau affinity against [H]OXD-2115, and in silico models were used to predict brain uptake. [F]OXD-2314 was identified as a selective, high-affinity non-AD tau PET radiotracer with favorable brain uptake, dosimetry, and radiometabolite profiles in rats and non-human primate and is being translated for first-in-human PET studies.
正电子发射断层扫描（PET）成像对阿尔茨海默病（AD）中 tau 聚集的研究有助于对 AD 病理的体内进展进行定位和定量。迄今为止，还没有专门针对非 AD tau 病的高亲和力 tau-PET 放射性药物进行优化。在这里，我们展示了基于配体设计的一类首创的 4R-tau 先导化合物[F]OXD-2115 的类似物的特性。我们合成了超过 150 种 OXD-2115 的类似物，并在死后脑组织中针对[H]OXD-2115 对 tau 的亲和力进行了筛选，还使用了计算机模型来预测脑摄取。[F]OXD-2314 被鉴定为一种选择性、高亲和力的非 AD tau PET 放射性示踪剂，在大鼠和非人类灵长类动物中具有良好的脑摄取、剂量学和放射性代谢产物特征，正在被转化为首次人体 PET 研究。
