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. 2019 Mar:83:242-249. doi: 10.1016/j.bioorg.2018.10.015. Epub 2018 Oct 17.

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 IC50 = 3.9 ± 1.2 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.

Keywords: AZD2461; Blood-brain barrier; MicroPET imaging; P-glycoprotein; PARP-1 inhibitor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / agonists
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • Animals
  • Blood-Brain Barrier / drug effects*
  • Cell Line, Tumor
  • Fluorine Radioisotopes / chemistry
  • Humans
  • Macaca mulatta
  • Male
  • Mice, Inbred BALB C
  • Phthalazines / chemical synthesis
  • Phthalazines / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / pharmacology*
  • Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • AZD2461
  • Fluorine Radioisotopes
  • Phthalazines
  • Piperidines
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1