Synthesis and evaluation of an AZD2461 [18F]PET probe in non-human primates reveals the PARP-1 inhibitor to be non-blood-brain barrier penetrant.
Bioorg Chem
; 83: 242-249, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30390553
ABSTRACT
Poly(ADP-ribose)polymerase-1 inhibitor (PARPi) AZD2461 was designed to be a weak P-glycoprotein (P-gp) analogue of FDA approved olaparib. With this chemical property in mind, we utilized the AZD2461 ligand architecture to develop a CNS penetrant and PARP-1 selective imaging probe, in order to investigate PARP-1 mediated neuroinflammation and neurodegenerative diseases, such as Alzheimer's and Parkinson's. Our work led to the identification of several high-affinity PARPi, including AZD2461 congener 9e (PARP-1 IC50â¯=â¯3.9⯱â¯1.2â¯nM), which was further evaluated as a potential 18F-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [18F]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ftalazinas
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Piperidinas
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Barreira Hematoencefálica
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Poli(ADP-Ribose) Polimerase-1
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos