Discovery and preclinical characterization of [
Alzheimer Disease
/ diagnostic imaging
Animals
Brain
/ diagnostic imaging
Fluorine Radioisotopes
/ pharmacokinetics
Humans
Macaca mulatta
Mice
Monoamine Oxidase
/ metabolism
Monoamine Oxidase Inhibitors
/ chemical synthesis
Positron-Emission Tomography
/ methods
Protein Binding
Pyridines
/ chemical synthesis
Radiopharmaceuticals
/ chemical synthesis
AD
Alzheimer’s disease
Fluorine-18
PET
PET tracer
PI-2620
Positron-emission tomography
Tau
Tauopathies
Journal
European journal of nuclear medicine and molecular imaging
ISSN: 1619-7089
Titre abrégé: Eur J Nucl Med Mol Imaging
Pays: Germany
ID NLM: 101140988
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
11
12
2018
accepted:
10
06
2019
pubmed:
3
7
2019
medline:
15
9
2020
entrez:
3
7
2019
Statut:
ppublish
Résumé
Tau deposition is a key pathological feature of Alzheimer's disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aβ) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies. Several PET tracers targeting tau deposits have been discovered and tested in humans. Limitations have been reported, especially regarding their selectivity. In our screening campaign we identified pyrrolo[2,3-b:4,5-c']dipyridine core structures with high affinity for aggregated tau. Further characterization showed that compounds containing this moiety had significantly reduced monoamine oxidase A (MAO-A) binding compared to pyrido[4,3-b]indole derivatives such as AV-1451. Here we present preclinical data of all ten fluoropyridine regioisomers attached to the pyrrolo[2,3-b:4,5-c']dipyridine scaffold, revealing compounds 4 and 7 with superior properties. The lead candidate [ Therefore, [
Identifiants
pubmed: 31264169
doi: 10.1007/s00259-019-04397-2
pii: 10.1007/s00259-019-04397-2
pmc: PMC6667408
doi:
Substances chimiques
((18)F)PI-2620
0
Fluorine Radioisotopes
0
Monoamine Oxidase Inhibitors
0
Pyridines
0
Radiopharmaceuticals
0
Monoamine Oxidase
EC 1.4.3.4
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2178-2189Références
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