Intracerebral Distribution of CAG Repeat-Binding Small Molecule Visualized by Whole-Brain Imaging.
Bioconjug Chem
; 34(12): 2187-2193, 2023 12 20.
Article
en En
| MEDLINE
| ID: mdl-37948852
ABSTRACT
Understanding the pharmacokinetics of drug candidates of interest in the brain and evaluating drug delivery to the brain are important for developing drugs targeting the brain. Previously, we demonstrated that a CAG repeat-binding small molecule, naphthyridine-azaquinolone (NA), resulted in repeat contraction in mouse models of dentatorubral-pallidoluysian atrophy and Huntington's disease caused by aberrant expansion of CAG repeats. However, the intracerebral distribution and drug deliverability of NA remain unclear. Here, we report three-dimensional whole-brain imaging of an externally administered small molecule using tissue clearing and light sheet fluorescence microscopy (LSFM). We designed and synthesized an Alexa594-labeled NA derivative with a primary amine for whole-brain imaging (NA-Alexa594-NH2), revealing the intracerebral distribution of NA-Alexa594-NH2 after intraparenchymal and intracerebroventricular administrations by whole-brain imaging combined with tissue clearing and LSFM. We also clarified that intranasally administered NA-Alexa594-NH2 was delivered into the brain via multiple nose-to-brain pathways by tracking the time-dependent change in the intracerebral distribution. Whole-brain imaging of small molecules by tissue clearing and LSFM is useful for elucidating not only the intracerebral distribution but also the drug delivery pathways into the brain.
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1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
/
Neuroimagen
Límite:
Animals
Idioma:
En
Revista:
Bioconjug Chem
Asunto de la revista:
BIOQUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Japón