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Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of...

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Autores principales: Herrmann, Frank, Hessmann, Manuela, Schaertl, Sabine, Berg-Rosseburg, Karola, Brown, Christopher J, Bursow, Galina, Chiki, Anass, Ebneth, Andreas, Gehrmann, Miriam, Hoeschen, Nicole, Hotze, Madlen, Jahn, Stefanie, Johnson, Peter D, Khetarpal, Vinod, Kiselyov, Alex, Kottig, Karsten, Ladewig, Stefanie, Lashuel, Hilal, Letschert, Sven, Mills, Matthew R, Petersen, Kathrin, Prime, Michael E, Scheich, Christoph, Schmiedel, Gerhard, Wityak, John, Liu, Longbin, Dominguez, Celia, Muñoz-Sanjuán, Ignacio, Bard, Jonathan A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429736/
https://www.ncbi.nlm.nih.gov/pubmed/34504195
http://dx.doi.org/10.1038/s41598-021-97334-z
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author Herrmann, Frank
Hessmann, Manuela
Schaertl, Sabine
Berg-Rosseburg, Karola
Brown, Christopher J
Bursow, Galina
Chiki, Anass
Ebneth, Andreas
Gehrmann, Miriam
Hoeschen, Nicole
Hotze, Madlen
Jahn, Stefanie
Johnson, Peter D
Khetarpal, Vinod
Kiselyov, Alex
Kottig, Karsten
Ladewig, Stefanie
Lashuel, Hilal
Letschert, Sven
Mills, Matthew R
Petersen, Kathrin
Prime, Michael E
Scheich, Christoph
Schmiedel, Gerhard
Wityak, John
Liu, Longbin
Dominguez, Celia
Muñoz-Sanjuán, Ignacio
Bard, Jonathan A
author_facet Herrmann, Frank
Hessmann, Manuela
Schaertl, Sabine
Berg-Rosseburg, Karola
Brown, Christopher J
Bursow, Galina
Chiki, Anass
Ebneth, Andreas
Gehrmann, Miriam
Hoeschen, Nicole
Hotze, Madlen
Jahn, Stefanie
Johnson, Peter D
Khetarpal, Vinod
Kiselyov, Alex
Kottig, Karsten
Ladewig, Stefanie
Lashuel, Hilal
Letschert, Sven
Mills, Matthew R
Petersen, Kathrin
Prime, Michael E
Scheich, Christoph
Schmiedel, Gerhard
Wityak, John
Liu, Longbin
Dominguez, Celia
Muñoz-Sanjuán, Ignacio
Bard, Jonathan A
author_sort Herrmann, Frank
collection PubMed
description Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.
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spelling pubmed-84297362021-09-13 Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates Herrmann, Frank Hessmann, Manuela Schaertl, Sabine Berg-Rosseburg, Karola Brown, Christopher J Bursow, Galina Chiki, Anass Ebneth, Andreas Gehrmann, Miriam Hoeschen, Nicole Hotze, Madlen Jahn, Stefanie Johnson, Peter D Khetarpal, Vinod Kiselyov, Alex Kottig, Karsten Ladewig, Stefanie Lashuel, Hilal Letschert, Sven Mills, Matthew R Petersen, Kathrin Prime, Michael E Scheich, Christoph Schmiedel, Gerhard Wityak, John Liu, Longbin Dominguez, Celia Muñoz-Sanjuán, Ignacio Bard, Jonathan A Sci Rep Article Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients. Nature Publishing Group UK 2021-09-09 /pmc/articles/PMC8429736/ /pubmed/34504195 http://dx.doi.org/10.1038/s41598-021-97334-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Herrmann, Frank
Hessmann, Manuela
Schaertl, Sabine
Berg-Rosseburg, Karola
Brown, Christopher J
Bursow, Galina
Chiki, Anass
Ebneth, Andreas
Gehrmann, Miriam
Hoeschen, Nicole
Hotze, Madlen
Jahn, Stefanie
Johnson, Peter D
Khetarpal, Vinod
Kiselyov, Alex
Kottig, Karsten
Ladewig, Stefanie
Lashuel, Hilal
Letschert, Sven
Mills, Matthew R
Petersen, Kathrin
Prime, Michael E
Scheich, Christoph
Schmiedel, Gerhard
Wityak, John
Liu, Longbin
Dominguez, Celia
Muñoz-Sanjuán, Ignacio
Bard, Jonathan A
Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
title Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
title_full Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
title_fullStr Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
title_full_unstemmed Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
title_short Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
title_sort pharmacological characterization of mutant huntingtin aggregate-directed pet imaging tracer candidates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429736/
https://www.ncbi.nlm.nih.gov/pubmed/34504195
http://dx.doi.org/10.1038/s41598-021-97334-z
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