Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core.
Alzheimer Disease
/ diagnosis
Brain
/ metabolism
Dose-Response Relationship, Drug
Humans
Molecular Structure
Monoamine Oxidase
/ metabolism
Nitrogen
/ chemistry
Positron-Emission Tomography
Pyridines
/ administration & dosage
Radiopharmaceuticals
/ chemistry
Structure-Activity Relationship
tau Proteins
/ analysis
Alzheimer’s disease
In silico
Pyridine derivatives
SAR
Tau-binding
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 12 2021
15 12 2021
Historique:
received:
09
09
2021
revised:
12
11
2021
accepted:
16
11
2021
pubmed:
29
11
2021
medline:
19
1
2022
entrez:
28
11
2021
Statut:
ppublish
Résumé
Tau aggregates represent a critical pathology in Alzheimer's disease (AD) and other forms of dementia. The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD. Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies. To evaluate the impact of the N-atom position with respect to Tau- and off-target binding, tricyclic core analogs of PI-2620 with nitrogen atoms at different positions were prepared. Affinity to aggregated Tau was evaluated using human AD brain homogenates, and their off-target binding was evaluated in a monoamine oxidase A (MAO-A) competition assay. The novel tricyclic core derivatives all displayed inferior Tau binding or MAO-A off-target selectivity, indicating PI-2620 to be the optimal design for high affinity binding to Tau and high MAO-A selectivity.
Identifiants
pubmed: 34839158
pii: S0968-0896(21)00536-8
doi: 10.1016/j.bmc.2021.116528
pii:
doi:
Substances chimiques
PI-2620
0
Pyridines
0
Radiopharmaceuticals
0
tau Proteins
0
Monoamine Oxidase
EC 1.4.3.4
Nitrogen
N762921K75
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
116528Informations de copyright
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