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)

被引：139

作者：

Walji, Abbas M. ^{[1
]}

Hostetler, Eric D. ^{[2
]}

Selnick, Harold ^{[1
]}

Zeng, Zhizhen ^{[2
]}

Miller, Patricia ^{[2
]}

Bennacef, Idriss ^{[2
]}

Salinas, Cristian ^{[2
]}

Connolly, Brett ^{[2
]}

Gantert, Liza ^{[2
]}

Holahan, Marie ^{[2
]}

O'Malley, Stacey ^{[2
]}

Purcell, Mona ^{[2
]}

Riffel, Kerry ^{[2
]}

Li, Jin ^{[3
]}

Balsells, Jaume ^{[3
]}

OBrien, Julie A. ^{[4
]}

Melquist, Stacey ^{[4
]}

Soriano, Aileen ^{[5
]}

Zhang, Xiaoping ^{[5
]}

Ogawa, Aimie ^{[5
]}

Xu, Serena ^{[5
]}

Joshi, Elizabeth ^{[6
]}

Della Rocca, Joseph ^{[7
]}

Hess, Fred J. ^{[8
]}

Schachter, Joel ^{[8
]}

Hesk, David

Schenk, David ^{[9
]}

Struyk, Arie ^{[10
]}

Babaoglu, Kerim ^{[11
]}

Lohith, Talakad G. ^{[2
]}

Wang, Yaode ^{[12
]}

Yang, Kun ^{[12
]}

Fu, Jianmin ^{[12
]}

Evelhoch, Jeffrey L. ^{[2
]}

Coleman, Paul J. ^{[1
]}

机构：

[1] Merck & Co Inc, Discovery Chem, West Point, PA 19486 USA

[2] Merck & Co Inc, Imaging, West Point, PA 19486 USA

[3] Merck & Co Inc, Proc Chem, West Point, PA 19486 USA

[4] Merck & Co Inc, Pharmacol, West Point, PA 19486 USA

[5] Merck & Co Inc, Pharmacol, Kenilworth, NJ 07033 USA

[6] Merck & Co Inc, Drug Metab, Kenilworth, NJ 07033 USA

[7] Merck & Co Inc, Discovery Pharmaceut Sci, Kenilworth, NJ 07033 USA

[8] Merck & Co Inc, Neurosci, Kenilworth, NJ 07033 USA

[9] Merck & Co Inc, Labelled Compound Synth, Rahway, NJ 07065 USA

[10] Merck & Co Inc, Clin Pharmacol, West Point, PA 19486 USA

[11] Merck & Co Inc, Computat Chem, West Point, PA 19486 USA

[12] Pharmaron Beijing Co Ltd, Beijing 100176, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 10期

关键词：

ALZHEIMERS-DISEASE; TAU PATHOLOGY; AMYLOID BURDEN; TRACER; BIOMARKERS; NEURODEGENERATION; PROGRESS; PLAQUES; BINDING; PROBES;

D O I：

10.1021/acs.jmedchem.6b00166

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-F-18)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([F-18]-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.

引用

页码：4778 / 4789

页数：12

共 51 条

[1] Staging of neurofibrillary pathology in Alzheimer's disease:: A study of the BrainNet Europe consortium [J].

Alafuzoff, Irina ;

Arzberger, Thomas ;

Al-Sarraj, Safa ;

Bodi, Istvan ;

Bogdanovic, Nenad ;

Braak, Heiko ;

Bugiani, Orso ;

Del-Tredici, Kelly ;

Ferrer, Isidro ;

Gelpi, Ellen ;

Giaccone, Giorgio ;

Graeber, Manuel B. ;

Ince, Paul ;

Kamphorst, Wouter ;

King, Andrew ;

Korkolopoulou, Penelope ;

Kovacs, Gabor G. ;

Larionov, Sergey ;

Meyronet, David ;

Monoranu, Camelia ;

Parchi, Piero ;

Patsouris, Efstratios ;

Roggendorf, Wolfgang ;

Seilhean, Danielle ;

Tagliavini, Fabrizio ;

Stadelmann, Christine ;

Streichenberger, Nathalie ;

Thal, Dietmar R. ;

Wharton, Stephen B. ;

Kretzschmar, Hans .

BRAIN PATHOLOGY, 2008, 18 (04) :484-496

[2] STRUCTURE AND NOVEL EXONS OF THE HUMAN-TAU GENE [J].

ANDREADIS, A ;

BROWN, WM ;

KOSIK, KS .

BIOCHEMISTRY, 1992, 31 (43) :10626-10633

[3] Tau Positron Emission Tomography (PET) Imaging: Past, Present, and Future [J].

Ariza, Manuela ;

Kolb, Hartmuth C. ;

Moechars, Dieder ;

Rombouts, Frederik ;

Ignacio Andres, Jose .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (11) :4365-4382

[4] NEUROFIBRILLARY TANGLES BUT NOT SENILE PLAQUES PARALLEL DURATION AND SEVERITY OF ALZHEIMERS-DISEASE [J].

ARRIAGADA, PV ;

GROWDON, JH ;

HEDLEYWHYTE, ET ;

HYMAN, BT .

NEUROLOGY, 1992, 42 (03) :631-639

[5] Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines As Imaging Agents for Tau Fibrils and β-Amyloid Plaques in Alzheimer's Disease Models [J].

Bolaender, Alexander ;

Kieser, Daniel ;

Voss, Constantin ;

Bauer, Silvia ;

Schoen, Christian ;

Burgold, Steffen ;

Bittner, Tobias ;

Hoelzer, Jana ;

Heyny-von Haussen, Roland ;

Mall, Gerhard ;

Goetschy, Valerie ;

Czech, Christian ;

Knust, Henner ;

Berger, Robert ;

Herms, Jochen ;

Hilger, Ingrid ;

Schmidtt, Boris .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (21) :9170-9180

[6] Frequency of stages of Alzheimer-related lesions in different age categories [J].

Braak, H ;

Braak, E .

NEUROBIOLOGY OF AGING, 1997, 18 (04) :351-357

[7]

Brendel M, 2014, J NUCL MED, V55

[8] Tau protein isoforms, phosphorylation and role in neurodegenerative disorders [J].

Buée, L ;

Bussière, T ;

Buée-Scherrer, V ;

Delacourte, A ;

Hof, PR .

BRAIN RESEARCH REVIEWS, 2000, 33 (01) :95-130

[9]

Buée L, 2002, MOVEMENT DISORD, V17, P1407

[10] Early Clinical PET Imaging Results with the Novel PHF-Tau Radioligand [F18]-T808 [J].

Chien, David T. ;

Szardenings, A. Katrin ;

Bahri, Shadfar ;

Walsh, Joseph C. ;

Mu, Fanrong ;

Xia, Chunfang ;

Shankle, William R. ;

Lerner, Alan J. ;

Su, Min-Ying ;

Elizarova, Arkadij ;

Kolb, Hartmuth C. .

JOURNAL OF ALZHEIMERS DISEASE, 2014, 38 (01) :171-184

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