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...
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Nature Portfolio
2021
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oai:doaj.org-article:9ab72a1e5e324d34b23c0110b93bbd782021-12-02T19:13:54ZPharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates10.1038/s41598-021-97334-z2045-2322https://doaj.org/article/9ab72a1e5e324d34b23c0110b93bbd782021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97334-zhttps://doaj.org/toc/2045-2322Abstract 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.Frank HerrmannManuela HessmannSabine SchaertlKarola Berg-RosseburgChristopher J BrownGalina BursowAnass ChikiAndreas EbnethMiriam GehrmannNicole HoeschenMadlen HotzeStefanie JahnPeter D JohnsonVinod KhetarpalAlex KiselyovKarsten KottigStefanie LadewigHilal LashuelSven LetschertMatthew R MillsKathrin PetersenMichael E PrimeChristoph ScheichGerhard SchmiedelJohn WityakLongbin LiuCelia DominguezIgnacio Muñoz-SanjuánJonathan A BardNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-19 (2021) |
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DOAJ |
| collection |
DOAJ |
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| topic |
Medicine R Science Q |
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Medicine R Science Q 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
pharmacological characterization of mutant huntingtin aggregate-directed pet imaging tracer candidates |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/9ab72a1e5e324d34b23c0110b93bbd78 |
| work_keys_str_mv |
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1718376988116254720 |