Discovery of 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2014) as PET tracer for the detection of pathological aggregated tau in Alzheimer's disease and other tauopathies.
Alzheimer Disease
/ diagnostic imaging
Animals
Brain
/ metabolism
Drug Discovery
Fluorine Radioisotopes
/ chemistry
Humans
Macaca mulatta
Mice
Molecular Structure
Positron-Emission Tomography
Primates
Protein Aggregates
Protein Binding
Radiopharmaceuticals
/ chemistry
Tauopathies
/ diagnostic imaging
tau Proteins
/ metabolism
Alzheimer disease
Fluorine-18
Neuroimaging
Positron emission tomography imaging
Tauopathies
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Oct 2020
15 Oct 2020
Historique:
received:
17
04
2020
revised:
04
06
2020
accepted:
21
06
2020
pubmed:
11
8
2020
medline:
22
5
2021
entrez:
11
8
2020
Statut:
ppublish
Résumé
The compound screening was initiated with a direct staining assay to identify compounds binding to Tau aggregates and not Abeta plaques using human brain sections derived from late stage Alzheimer's disease donors. The binding of Tau aggregate selective compounds was then quantitatively assessed with human brain derived paired helical filaments utilizing the label-free Back Scattering Interferometry assay. In vivo biodistribution experiments of selected fluorine-18 labeled compounds were performed in mice to assess brain uptake, brain washout, and defluorination. Compound 11 emerged as the most promising candidate, displaying high in vitro binding affinity and selectivity to neurofibrillary tangles. Fluorine-18 labeled compound 11 showed high brain uptake and rapid washout from the mouse brain with no observed bone uptake. Furthermore, compound 11 was able to detect Tau aggregates in tauopathy brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick's disease donors. Thus, 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c']dipyridine (PI-2014, compound 11) was selected for characterization in a first-in-human study.
Identifiants
pubmed: 32771872
pii: S0223-5234(20)30587-0
doi: 10.1016/j.ejmech.2020.112615
pii:
doi:
Substances chimiques
Fluorine Radioisotopes
0
Protein Aggregates
0
Radiopharmaceuticals
0
tau Proteins
0
Fluorine-18
GZ5I74KB8G
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
112615Informations de copyright
Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Emanuele Gabellieri, Heiko Kroth, Francesca Capotosti, Jerome Molette, Nampally Sreenivasachary, Tanja Juergens, Yvan Varisco, David Hickman, Andrea Pfeifer are employees of AC Immune SA. Andre Mueller, Mathias Berndt, Felix Oden, Heribert Schmitt-Willich, Ludger Dinkelborg, Andrew Stephens are employees of Life Molecular Imaging GmbH. Hanno Schieferstein was an employee of Piramal Imaging GmbH (currently at Merck KGaA).