High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer's Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection
High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer's Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection
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DOI：
10.1021/cn500103u
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发表时间：
2014-08-01
影响因子：
5
通讯作者：
Scott, Peter J. H.
中科院分区：
文献类型：
--
作者：
Fawaz, Maria V.;Brooks, Allen F.;Scott, Peter J. H.
异常聚集的tau是tau蛋白病神经退行性疾病的标志性病理学，并且是开发整个tau蛋白病疾病谱的诊断工具和治疗策略的靶标。开发对tau具有适当亲和力和特异性的碳-11-或氟-18-标记的放射性示踪剂将允许使用正电子发射断层扫描（PET）成像对tau负荷进行无创定量。我们合成了[F-18]兰索拉唑、[C-11] N-甲基兰索拉唑和[F-18] N-甲基兰索拉唑，并将其鉴定为tau的高亲和力放射性示踪剂，结合亲和力低至亚纳摩尔。在此，我们报告放射合成和广泛的临床前评价，目的是选择一种用于人体PET成像试验的铅放射性示踪剂。我们证明，由于氟-18的半衰期有利，其在非人灵长类动物中快速进入大脑，动力学有利，低白色物质结合，以及选择性结合tau蛋白而不是淀粉样蛋白，[F-18] N-甲基兰索拉唑是进入临床试验的主要化合物。
Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [F-18]lansoprazole, [C-11]N-methyl lansoprazole, and [F-18]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [F-18] N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.