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Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer’s Disease with Positron Emission Tomography
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-12 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00632 Luca C. Gobbi 1 , Henner Knust 1 , Matthias Körner 1 , Michael Honer 1 , Christian Czech 1 , Sara Belli 1 , Dieter Muri 1 , Martin R. Edelmann 1 , Thomas Hartung 1 , Isabella Erbsmehl 1 , Sandra Grall-Ulsemer 1 , Andreas Koblet 1 , Marianne Rueher 1 , Sandra Steiner 1 , Hayden T. Ravert , William B. Mathews , Daniel P. Holt , Hiroto Kuwabara , Heather Valentine , Robert F. Dannals , Dean F. Wong , Edilio Borroni 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-12 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00632 Luca C. Gobbi 1 , Henner Knust 1 , Matthias Körner 1 , Michael Honer 1 , Christian Czech 1 , Sara Belli 1 , Dieter Muri 1 , Martin R. Edelmann 1 , Thomas Hartung 1 , Isabella Erbsmehl 1 , Sandra Grall-Ulsemer 1 , Andreas Koblet 1 , Marianne Rueher 1 , Sandra Steiner 1 , Hayden T. Ravert , William B. Mathews , Daniel P. Holt , Hiroto Kuwabara , Heather Valentine , Robert F. Dannals , Dean F. Wong , Edilio Borroni 1
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Aggregates of tau and beta amyloid (Aβ) plaques constitute the histopathological hallmarks of Alzheimer’s disease and are prominent targets for novel therapeutics as well as for biomarkers for diagnostic in vivo imaging. In recent years much attention has been devoted to the discovery and development of new PET tracers to image tau aggregates in the living human brain. Access to a selective PET tracer to image and quantify tau aggregates represents a unique tool to support the development of any novel therapeutic agent targeting pathological forms of tau. The objective of the study described herein was to identify such a novel radiotracer. As a result of this work, we discovered three novel PET tracers (2-(4-[11C]methoxyphenyl)imidazo[1,2-a]pyridin-7-amine 7 ([11C]RO6924963), N-[11C]methyl-2-(3-methylphenyl)imidazo[1,2-a]pyrimidin-7-amine 8 ([11C]RO6931643), and [18F]2-(6-fluoropyridin-3-yl)pyrrolo[2,3-b:4,5-c′]dipyridine 9 ([18F]RO6958948)) with high affinity for tau neurofibrillary tangles, excellent selectivity against Aβ plaques, and appropriate pharmacokinetic and metabolic properties in mice and non-human primates.
中文翻译：
正电子发射断层显像技术鉴定三种新型放射性示踪剂，用于在阿尔茨海默氏病中对聚集的Tau成像
tau和β淀粉样蛋白（Aβ）斑块的聚集体构成了阿尔茨海默氏病的组织病理学标志，是新型疗法以及用于体内诊断的生物标志物的重要靶标。近年来，人们对新型PET示踪剂的发现和开发投入了大量精力，以描绘人脑中tau聚集体的图像。获得选择性PET示踪剂以成像和定量tau聚集体的方法代表了一种独特的工具，可支持针对tau病理形式的任何新型治疗剂的开发。本文所述研究的目的是鉴定这种新颖的放射性示踪剂。这项工作的结果是，我们发现了三种新颖的PET示踪剂（2-（4- [ 11 [ C]甲氧基苯基]咪唑并[1,2- a ]吡啶7-胺7]（[ 11 C] RO6924963），N- [ 11 C]甲基-2-（3-甲基苯基）咪唑并[1,2- a ]嘧啶-7-胺8（[ 11 C] RO6931643）和[ 18 F]对tau神经原纤维缠结具有高亲和力的2-（6-氟吡啶-3--3-基）吡咯并[2,3- b：4,5- c ']双吡啶9（[ 18 F] RO6958948）），对Aβ斑块的选择性极好，以及小鼠和非人类灵长类动物的适当药代动力学和代谢特性。
更新日期：2017-07-13
中文翻译：
正电子发射断层显像技术鉴定三种新型放射性示踪剂，用于在阿尔茨海默氏病中对聚集的Tau成像
tau和β淀粉样蛋白（Aβ）斑块的聚集体构成了阿尔茨海默氏病的组织病理学标志，是新型疗法以及用于体内诊断的生物标志物的重要靶标。近年来，人们对新型PET示踪剂的发现和开发投入了大量精力，以描绘人脑中tau聚集体的图像。获得选择性PET示踪剂以成像和定量tau聚集体的方法代表了一种独特的工具，可支持针对tau病理形式的任何新型治疗剂的开发。本文所述研究的目的是鉴定这种新颖的放射性示踪剂。这项工作的结果是，我们发现了三种新颖的PET示踪剂（2-（4- [ 11 [ C]甲氧基苯基]咪唑并[1,2- a ]吡啶7-胺7]（[ 11 C] RO6924963），N- [ 11 C]甲基-2-（3-甲基苯基）咪唑并[1,2- a ]嘧啶-7-胺8（[ 11 C] RO6931643）和[ 18 F]对tau神经原纤维缠结具有高亲和力的2-（6-氟吡啶-3--3-基）吡咯并[2,3- b：4,5- c ']双吡啶9（[ 18 F] RO6958948）），对Aβ斑块的选择性极好，以及小鼠和非人类灵长类动物的适当药代动力学和代谢特性。
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