Journal
BIOORGANIC CHEMISTRY
Volume 83, Issue -, Pages 242-249Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2018.10.015
Keywords
PARP-1 inhibitor; MicroPET imaging; P-glycoprotein; Blood-brain barrier; AZD2461
Funding
- [5T32DA028874-07]
- [T32GM008076]
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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 IC50, = 3.9 +/- 1.2 nM), which was further evaluated as a potential F-18-PET brain imaging probe. However, despite the similar molecular scaffolds of 9e and AZD2461, our studies revealed non-appreciable brain-uptake of [F-18]9e in non-human primates, suggesting AZD2461 to be non-CNS penetrant.
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