Discovery of 6‑(Fluoro-¹⁸<i>F</i>)‑3-(1<i>H</i>‑pyrrolo[2,3‑<i>c</i>]pyridin-1-yl)isoquinolin-5-amine ([¹⁸F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer’s disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-18F)-3-(1H-pyrrolo­[2,3-c]­pyridin-1-yl)­isoquinolin-5-amine, 6 ([18F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.神经原纤维缠结（Neurofibrillary tangles, NFTs）由聚集的tau蛋白构成，已被确定为包括阿尔茨海默病在内的多种神经退行性疾病的病理标志性特征。采用正电子发射断层扫描（Positron Emission Tomography, PET）成像对NFTs进行体内检测，可为开发药效学工具以加速靶向tau病理的新型疾病修饰治疗药物的研发提供独特契机。本文报道了6-(氟-18F)-3-(1H-吡咯并[2,3-c]吡啶-1-基)异喹啉-5-胺（化合物6，[18F]-MK-6240）的发现，其作为一种新型PET示踪剂可用于检测NFTs。该化合物对NFTs的结合具有高特异性和选择性，同时具备适宜的理化性质与体内药代动力学特性。