551001-79-7Relevant academic research and scientific papers
Potential Diagnostic Imaging of Alzheimer's Disease with Copper-64 Complexes That Bind to Amyloid-β Plaques
McInnes, Lachlan E.,Noor, Asif,Kysenius, Kai,Cullinane, Carleen,Roselt, Peter,McLean, Catriona A.,Chiu, Francis C. K.,Powell, Andrew K.,Crouch, Peter J.,White, Jonathan M.,Donnelly, Paul S.
, (2019)
Amyloid-β plaques, consisting of aggregated amyloid-β peptides, are one of the pathological hallmarks of Alzheimer's disease. Copper complexes formed using positron-emitting copper radionuclides that cross the blood-brain barrier and bind to specific molecular targets offer the possibility of noninvasive diagnostic imaging using positron emission tomography. New thiosemicarbazone-pyridylhydrazone based ligands that incorporate pyridyl-benzofuran functional groups designed to bind amyloid-β plaques have been synthesized. The ligands form stable complexes with copper(II) (Kd = 10-18 M) and can be radiolabeled with copper-64 at room temperature. Subtle changes to the periphery of the ligand backbone alter the metabolic stability of the complexes in mouse and human liver microsomes, and influenced the ability of the complexes to cross the blood-brain barrier in mice. A lead complex was selected based on possessing the best metabolic stability and brain uptake in mice. Synthesis of this lead complex with isotopically enriched copper-65 allowed us to show that the complex bound to amyloid-β plaques present in post-mortem human brain tissue using laser ablation-inductively coupled plasma-mass spectrometry. This work provides insight into strategies to target metal complexes to amyloid-β plaques, and how small modifications to ligands can dramatically alter the metabolic stability of metal complexes as well as their ability to cross the blood-brain barrier.
Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand
Prime, Michael E.,Liu, Longbin,Lee, Matt R.,Khetarpal, Vinod,Brown, Christopher J.,Johnson, Peter D.,Miranda-Azpiazu, Patricia,Chen, Xuemei,Clark-Frew, Daniel,Coe, Samuel,Davis, Randall,Dickie, Anthony,Ebneth, Andreas,Esposito, Simone,Gadouleau, Elise,Gai, Xinjie,Galan, Sebastien,Green, Samantha,Greenaway, Catherine,Giles, Paul,Halldin, Christer,Hayes, Sarah,Herbst, Todd,Herrmann, Frank,He?mann, Manuela,Jia, Zhisheng,Kiselyov, Alexander,Kotey, Adrian,Krulle, Thomas,Mangette, John E.,Marston, Richard W.,Menta, Sergio,Mills, Matthew R.,Monteagudo, Edith,Nag, Sangram,Nibbio, Martina,Orsatti, Laura,Schaertl, Sabine,Scheich, Christoph,Sproston, Joanne,Stepanov, Vladimir,Svedberg, Marie,Takano, Akihiro,Taylor, Malcolm,Thomas, Wayne,Toth, Miklós,Vaidya, Darshan,Vanr?s, Katarina,Weddell, Derek,Wigginton, Ian,Wityak, John,Mrzljak, Ladislav,Munoz-Sanjuan, Ignacio,Bard, Jonathan A.,Dominguez, Celia
, p. 8608 - 8633 (2020/09/16)
Mutant huntingtin (mHTT) protein carrying the elongated N-Terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-Affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.
BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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Page/Page column 292; 397, (2018/03/25)
Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
Rhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-β plaques
Fletcher, Scott P.,Noor, Asif,Hickey, James L.,McLean, Catriona A.,White, Jonathan M.,Donnelly, Paul S.
, p. 1139 - 1151 (2018/07/13)
Abstract: Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99?m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]3+ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-β targeting functional groups. The interaction of the [Re-oxo]3+ complexes with synthetic amyloid-β1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [99mTc-oxo]3+ complexes at the tracer level. These technetium-99?m complexes are likely to be isostructural to their rhenium-oxo analogues.
PROBES FOR IMAGING HUNTINGTIN PROTEIN
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Paragraph 0379, (2016/03/22)
Provided are imaging agents comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of their use.
PROBES FOR IMAGING HUNTINGTIN PROTEIN
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Paragraph 0149, (2016/03/22)
Provided are imaging agents comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of their use.
DIARYLETHENE COMPOUNDS AND USES THEREOF
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Paragraph 0347, (2014/09/29)
A compound according to Formula IA and IB, reversibly convertible under photochromic and electrochromic conditions between a ring-open isomer A and a ring-closed isomer B is provided. For substitutent groups, Z is N, O or S; each R1 is independently selected from the group consisting of H, or halo; each R2 is independently selected from the group consisting of H, halo, a polymer backbone, alkyl or aryl; or, when both R2 together form —CH═CH— and form part of a polymer backbone; each R3 is independently selected from the group consisting of H, halo, alkyl, alkoxy, thioalkyl or aryl; each R4 is aryl; and each R5 is independently selected from the group consisting of H, halo, alkyl, alkoxy, thioalkyl or aryl.
HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Page/Page column 63, (2012/09/21)
Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
Synthesis and evaluation of 2-pyridylbenzothiazole, 2-pyridylbenzoxazole and 2-pyridylbenzofuran derivatives as 11C-PET imaging agents for β-amyloid plaques
Swahn, Britt-Marie,Wensbo, David,Sandell, Johan,Sohn, Daniel,Slivo, Can,Pyring, David,Malmstr?m, Jonas,Arzel, Erwan,Vallin, Michaela,Bergh, Margareta,Jeppsson, Fredrik,Johnson, Allan E.,Juréus, Anders,Neelissen, Jan,Svensson, Samuel
scheme or table, p. 1976 - 1980 (2010/07/07)
The syntheses and SAR of new series of β-amyloid binding agents are reported. The effort to optimize signal-to-background ratios for these ligands are described. Compounds 8, 21 and 30 displayed desirable lipophilicity and pharmacokinetic properties. Compounds 8 and 21 were evaluated with in vitro autoradiographic studies and in vivo in APP/PS1 transgenic mice. It is shown that it was possible to increase the signal-to-background ratios compared to PIB 1, as demonstrated by compounds 8 and 21.
NOVEL 2-HETEROARYL SUBSTITUTED BENZOTHIOPHENES AND BENZOFURANES 709
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Page/Page column 19, (2008/12/08)
The present invention relates to novel 2-heteroaryl substituted benzothiophene and benzofuran derivatives, precursors thereof, and therapeutic uses of such compounds, having the structural formula (Ia) below: and to their pharmaceutically acceptable salt, compositions and methods of use. Furthermore, the invention relates to novel 2-heteroaryl substituted benzothiophene and benzofuran derivatives that are suitable for imaging amyloid deposits in living patients, their compositions, methods of use and processes to make such compounds. More specifically, the present invention relates to a method of imaging amyloid deposits in brain in vivo to allow antemortem diagnosis of Alzheimers disease as well as measureing clinical efficacy of Alzheimers disease therapeutic agents.
