Dataset Information

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 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.

SUBMITTER: Herrmann F

PROVIDER: S-EPMC8429736 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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

Herrmann Frank F Hessmann Manuela M Schaertl Sabine S Berg-Rosseburg Karola K Brown Christopher J CJ Bursow Galina G Chiki Anass A Ebneth Andreas A Gehrmann Miriam M Hoeschen Nicole N Hotze Madlen M Jahn Stefanie S Johnson Peter D PD Khetarpal Vinod V Kiselyov Alex A Kottig Karsten K Ladewig Stefanie S Lashuel Hilal H Letschert Sven S Mills Matthew R MR Petersen Kathrin K Prime Michael E ME Scheich Christoph C Schmiedel Gerhard G Wityak John J Liu Longbin L Dominguez Celia C Muñoz-Sanjuán Ignacio I Bard Jonathan A JA

Scientific reports 20210909 1

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 ...[more]

PMID: 34504195

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Dataset Information

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

Publications

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

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