[ 18 F]-SuPAR: A Radiofluorinated Probe for Noninvasive Imaging of DNA Damage-Dependent Poly(ADP-ribose) Polymerase Activity

Bioconjug Chem. 2019 May 15;30(5):1331-1342. doi: 10.1021/acs.bioconjchem.9b00089. Epub 2019 Apr 22.

Abstract

Poly(ADP ribose) polymerase (PARP) enzymes generate poly(ADP ribose) post-translational modifications on target proteins for an array of functions centering on DNA and cell stress. PARP isoforms 1 and 2 are critically charged with the surveillance of DNA integrity and are the first line guardians of the genome against DNA breaks. Here we present a novel probe ([18F]-SuPAR) for noninvasive imaging of PARP-1/2 activity using positron emission tomography (PET). [18F]-SuPAR is a radiofluorinated nicotinamide adenine dinucleotide (NAD) analog that can be recognized by PARP-1/2 and incorporated into the long branched polymers of poly(ADP ribose) (PAR). The measurement of PARP-1/2 activity was supported by a reduction of radiotracer uptake in vivo following PARP-1/2 inhibition with talazoparib treatment, a potent PARP inhibitor recently approved by FDA for treatment of breast cancer, as well as ex vivo colocalization of radiotracer analog and poly(ADP ribose). With [18F]-SuPAR, we were able to map the dose- and time-dependent activation of PARP-1/2 following radiation therapy in breast and cervical cancer xenograft mouse models. Tumor response to therapy was determined by [18F]-SuPAR PET within 8 h of administration of a single dose of radiation equivalent to one round of stereotactic ablative radiotherapy.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / diagnostic imaging
  • DNA Damage*
  • Female
  • Fluorine Radioisotopes / administration & dosage*
  • Humans
  • NAD / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Positron-Emission Tomography
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Substrate Specificity
  • Uterine Cervical Neoplasms / diagnostic imaging
  • Xenograft Model Antitumor Assays

Substances

  • Fluorine Radioisotopes
  • Receptors, Urokinase Plasminogen Activator
  • NAD
  • Poly(ADP-ribose) Polymerases