Synthesis, [¹⁸F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography

Bioorg Med Chem. 2014 Mar 1;22(5):1700-7. doi: 10.1016/j.bmc.2014.01.019. Epub 2014 Jan 24.

Abstract

Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be (18)F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50=6.3 nM). [(18)F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [(18)F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [(18)F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [(18)F]12 in the tumor is specific to PARP-1 expression.

Keywords: Imaging; PARP-1; PET; Radiolabeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Mice
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Positron-Emission Tomography / methods*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Poly(ADP-ribose) Polymerases