Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-09-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-97334-z |
| _version_ | 1818742510522990592 |
|---|---|
| author | Frank Herrmann Manuela Hessmann Sabine Schaertl Karola Berg-Rosseburg Christopher J Brown Galina Bursow Anass Chiki Andreas Ebneth Miriam Gehrmann Nicole Hoeschen Madlen Hotze Stefanie Jahn Peter D Johnson Vinod Khetarpal Alex Kiselyov Karsten Kottig Stefanie Ladewig Hilal Lashuel Sven Letschert Matthew R Mills Kathrin Petersen Michael E Prime Christoph Scheich Gerhard Schmiedel John Wityak Longbin Liu Celia Dominguez Ignacio Muñoz-Sanjuán Jonathan A Bard |
| author_facet | Frank Herrmann Manuela Hessmann Sabine Schaertl Karola Berg-Rosseburg Christopher J Brown Galina Bursow Anass Chiki Andreas Ebneth Miriam Gehrmann Nicole Hoeschen Madlen Hotze Stefanie Jahn Peter D Johnson Vinod Khetarpal Alex Kiselyov Karsten Kottig Stefanie Ladewig Hilal Lashuel Sven Letschert Matthew R Mills Kathrin Petersen Michael E Prime Christoph Scheich Gerhard Schmiedel John Wityak Longbin Liu Celia Dominguez Ignacio Muñoz-Sanjuán Jonathan A Bard |
| author_sort | Frank Herrmann |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-18T02:13:40Z |
| format | Article |
| id | doaj.art-9ab72a1e5e324d34b23c0110b93bbd78 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T02:13:40Z |
| publishDate | 2021-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-9ab72a1e5e324d34b23c0110b93bbd782022-12-21T21:24:26ZengNature PortfolioScientific Reports2045-23222021-09-0111111910.1038/s41598-021-97334-zPharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidatesFrank Herrmann0Manuela Hessmann1Sabine Schaertl2Karola Berg-Rosseburg3Christopher J Brown4Galina Bursow5Anass Chiki6Andreas Ebneth7Miriam Gehrmann8Nicole Hoeschen9Madlen Hotze10Stefanie Jahn11Peter D Johnson12Vinod Khetarpal13Alex Kiselyov14Karsten Kottig15Stefanie Ladewig16Hilal Lashuel17Sven Letschert18Matthew R Mills19Kathrin Petersen20Michael E Prime21Christoph Scheich22Gerhard Schmiedel23John Wityak24Longbin Liu25Celia Dominguez26Ignacio Muñoz-Sanjuán27Jonathan A Bard28Evotec SEEvotec SEEvotec SEEvotec SEEvotec (U.K.) Ltd.Evotec SELaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)Evotec SEEvotec SEEvotec SEEvotec SEEvotec SEEvotec (U.K.) Ltd.CHDI Management/CHDI FoundationCHDI Management/CHDI FoundationEvotec SEEvotec SELaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)Evotec SEEvotec (U.K.) Ltd.Evotec SEEvotec (U.K.) Ltd.Evotec SEEvotec SECHDI Management/CHDI FoundationCHDI Management/CHDI FoundationCHDI Management/CHDI FoundationCHDI Management/CHDI FoundationCHDI Management/CHDI FoundationAbstract 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.https://doi.org/10.1038/s41598-021-97334-z |
| spellingShingle | Frank Herrmann Manuela Hessmann Sabine Schaertl Karola Berg-Rosseburg Christopher J Brown Galina Bursow Anass Chiki Andreas Ebneth Miriam Gehrmann Nicole Hoeschen Madlen Hotze Stefanie Jahn Peter D Johnson Vinod Khetarpal Alex Kiselyov Karsten Kottig Stefanie Ladewig Hilal Lashuel Sven Letschert Matthew R Mills Kathrin Petersen Michael E Prime Christoph Scheich Gerhard Schmiedel John Wityak Longbin Liu Celia Dominguez Ignacio Muñoz-Sanjuán Jonathan A Bard Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-021-97334-z |
| work_keys_str_mv | AT frankherrmann pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT manuelahessmann pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT sabineschaertl pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT karolabergrosseburg pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT christopherjbrown pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT galinabursow pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT anasschiki pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT andreasebneth pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT miriamgehrmann pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT nicolehoeschen pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT madlenhotze pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT stefaniejahn pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT peterdjohnson pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT vinodkhetarpal pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT alexkiselyov pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT karstenkottig pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT stefanieladewig pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT hilallashuel pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT svenletschert pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT matthewrmills pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT kathrinpetersen pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT michaeleprime pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT christophscheich pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT gerhardschmiedel pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT johnwityak pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT longbinliu pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT celiadominguez pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT ignaciomunozsanjuan pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates AT jonathanabard pharmacologicalcharacterizationofmutanthuntingtinaggregatedirectedpetimagingtracercandidates |