- An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans
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[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetr
- Huang, Ya-Yao,Chiu, Ming-Jang,Yen, Ruoh-Fang,Tsai, Chia-Ling,Hsieh, Hao-Yu,Chiu, Ching-Hung,Wu, Chi-Han,Hsin, Ling-Wei,Tzen, Kai-Yuan,Cheng, Cheng-Yi,Ma, Kuo-Hsing,Shiue, Chyng-Yann
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Read Online
- Discovery of 6-(Fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)
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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 opportuni
- Walji, Abbas M.,Hostetler, Eric D.,Selnick, Harold,Zeng, Zhizhen,Miller, Patricia,Bennacef, Idriss,Salinas, Cristian,Connolly, Brett,Gantert, Liza,Holahan, Marie,O'Malley, Stacey,Purcell, Mona,Riffel, Kerry,Li, Jing,Balsells, Jaume,Obrien, Julie A.,Melquist, Stacey,Soriano, Aileen,Zhang, Xiaoping,Ogawa, Aimie,Xu, Serena,Joshi, Elizabeth,Della Rocca, Joseph,Hess, Fred J.,Schachter, Joel,Hesk, David,Schenk, David,Struyk, Arie,Babaoglu, Kerim,Lohith, Talakad G.,Wang, Yaode,Yang, Kun,Fu, Jianmin,Evelhoch, Jeffrey L.,Coleman, Paul J.
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Read Online
- PI-2620 Lead Optimization Highlights the Importance of Off-Target Assays to Develop a PET Tracer for the Detection of Pathological Aggregated Tau in Alzheimer's Disease and Other Tauopathies
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The first candidate PI-2014 was tested in healthy controls and subjects with Alzheimer's disease (AD). As PI-2014 displayed off-target binding to monoamine oxidase A (MAO-A), a new lead with improved binding to Tau and decreased MAO-A binding was required. For compound optimization, Tau binding assays based on both human AD brain homogenate and Tau-paired helical filaments were employed. Furthermore, two MAO-A screening assays based on (1) human-recombinant MAO-A and (2) displacement of 2-fluoro-ethyl-harmine from mouse brain homogenate were employed. Removing the N-methyl group from the tricyclic core resulted in compounds displaying improved Tau binding. For the final round of optimization, the cyclic amine substituents were replaced by pyridine derivatives. PI-2620 (2-(2-fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c′]dipyridine) emerged as a best candidate displaying high Tau binding, low MAO-A binding, high brain uptake, and fast and complete brain washout. Furthermore, PI-2620 showed Tau binding on brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick's disease.
- Berndt, Mathias,Capotosti, Francesca,Dinkelborg, Ludger,Gabellieri, Emanuele,Hickman, David,Kroth, Heiko,Molette, Jerome,Mueller, Andre,Oden, Felix,Pfeifer, Andrea,Schieferstein, Hanno,Schmitt-Willich, Heribert,Serra, Andreia Monica,Sreenivasachary, Nampally,Stephens, Andrew
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p. 12808 - 12830
(2021/09/13)
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- TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0382; 0383
(2021/02/12)
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- Novel compounds useful as fluorescent probes selectively binding to tau aggregates and preparation method thereof
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A compound having high selectivity for tau aggregates and a method for preparing the same. The present invention relates to a tau targeting fluorescent probe including the compound, a composition for detecting tau fiber protein comprising the fluorescent
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- GAMMA-CARBOLINE COMPOUNDS FOR THE DETECTION OF TAU AGGREGATES
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The present invention relates to novel compounds of the formula (II) and formula (III) that can be employed in the selective Tau detection of disorders and abnormalities associated with Tau aggregates such as Alzheimer's disease and other tauopathies using Positron Emission Tomography (PET) Imaging.
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Page/Page column 27
(2019/08/12)
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- TAU-PROTEIN TARGETING PROTACS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of tau protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tau protein, such that tau protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tau. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tau protein. Diseases or disorders that result from aggregation or accumulation of tau protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0675-0676
(2018/05/24)
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- Identification of Three Novel Radiotracers for Imaging Aggregated Tau in Alzheimer's Disease with Positron Emission Tomography
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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.
- Gobbi, Luca C.,Knust, Henner,K?rner, Matthias,Honer, Michael,Czech, Christian,Belli, Sara,Muri, Dieter,Edelmann, Martin R.,Hartung, Thomas,Erbsmehl, Isabella,Grall-Ulsemer, Sandra,Koblet, Andreas,Rueher, Marianne,Steiner, Sandra,Ravert, Hayden T.,Mathews, William B.,Holt, Daniel P.,Kuwabara, Hiroto,Valentine, Heather,Dannals, Robert F.,Wong, Dean F.,Borroni, Edilio
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p. 7350 - 7370
(2017/09/22)
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- Synthesis method of diagnosis and treatment integrated target prodrug for AD (Alzheimer's disease) tau protein
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As an indole drug, T807 is widely applied to a PET tracer agent of AD due to the characteristics of high selectivity and affinity of combination with tau protein, good biological distribution in animal bodies, less retention in white matter, stable uptake
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Paragraph 0021; 0022
(2017/05/27)
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- Fully automated synthesis of [18F]T807, a PET tau tracer for Alzheimer's disease
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The authentic standard T807 and its nitro-precursor T807P as well as t-Boc-protected T807P precursor for radiolabeling were synthesized from (4-bromophenyl)boronic acid, 3-bromo-4-nitropyridine and 3-bromo-6-nitropyridine with overall chemical yield 27% i
- Gao, Mingzhang,Wang, Min,Zheng, Qi-Huang
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p. 2953 - 2957
(2015/06/22)
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- Microwave-enhanced Fischer reaction: An efficient one-pot synthesis of γ-carbolines
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γ-Carbolines were obtained in a simple one-pot Fischer reaction starting from N-acetyl-3-bromo-4-piperidone hydrobromide and substituted arylhydrazine hydrochlorides in acidic media under microwave irradiation or by a thermal process. The optimization procedures are reported in detail, and the results from microwave processes are compared with conventional ones. Georg Thieme Verlag Stuttgart.
- Chen, Jing,Chen, Weiliang,Hu, Yongzhou
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