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

Alzheimer Disease / metabolism Animals Autoradiography / methods Brain / metabolism Disease Models, Animal Humans Huntingtin Protein / genetics Huntington Disease / metabolism Immunohistochemistry / methods Mice Mice, Transgenic Nitrogen Radioisotopes / metabolism Positron-Emission Tomography / methods Protein Aggregates / genetics Protein Aggregation, Pathological / diagnostic imaging Radioactive Tracers Radioligand Assay / methods Radiopharmaceuticals / metabolism Recombinant Proteins / metabolism

Journal

Scientific reports

ISSN: 2045-2322

Titre abrégé: Sci Rep

Pays: England

ID NLM: 101563288

Informations de publication

Date de publication:
09 09 2021

Historique:

received: 18 06 2021

accepted: 24 08 2021

entrez: 10 9 2021

pubmed: 11 9 2021

medline: 18 11 2021

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41598-021-97334-z PMID: 34504195 PMC: PMC8429736

pubmed: 34504195

doi: 10.1038/s41598-021-97334-z

pii: 10.1038/s41598-021-97334-z

pmc: PMC8429736

doi:

Substances chimiques

HTT protein, human 0

Htt protein, mouse 0

Huntingtin Protein 0

Nitrogen Radioisotopes 0

Protein Aggregates 0

Radioactive Tracers 0

Radiopharmaceuticals 0

Recombinant Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

17977

Informations de copyright

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