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Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates
- Source :
- Scientific Reports, Vol 11, Iss 1, Pp 1-19 (2021), Scientific Reports
- Publication Year :
- 2021
- Publisher :
- Nature Portfolio, 2021.
-
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.
- Subjects :
- exon-1
Huntingtin
Mutant
law.invention
Mice
Radioligand Assay
amyloid fibrils
Exon
law
alzheimers-disease
Huntingtin Protein
dysfunction
Multidisciplinary
Chemistry
Immunohistochemistry
Recombinant Proteins
Cell biology
small molecules
Huntington Disease
Recombinant DNA
Medicine
Preclinical imaging
congenital, hereditary, and neonatal diseases and abnormalities
brain
Science
Mice, Transgenic
Protein Aggregation, Pathological
Article
Protein Aggregates
Alzheimer Disease
mental disorders
Animals
Humans
Radioactive Tracers
beta-sheet structure
Pharmacology
Nitrogen Radioisotopes
toxicity
In vitro
nervous system diseases
Disease Models, Animal
polyglutamine aggregation
Positron-Emission Tomography
Diseases of the nervous system
Autoradiography
identification
Radiopharmaceuticals
Trinucleotide repeat expansion
Biomarkers
Ex vivo
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....a157f6eee06d07d3c18e1c6daf1e927b