PET Imaging of PARP Expression Using 18 F-Olaparib

J Nucl Med. 2019 Apr;60(4):504-510. doi: 10.2967/jnumed.118.213223. Epub 2018 Nov 2.

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18F-radiolabeled isotopolog of the Food and Drug Administration-approved PARP inhibitor olaparib. The use of the 18F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results: 18F-olaparib was taken up selectively in vitro in PARP-1-expressing cells. Irradiation increased PARP-1 expression and 18F-olaparib uptake in a radiation-dose-dependent fashion. PET imaging in mice showed specific uptake of 18F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18F-olaparib increased by 70% (P = 0.025). Conclusion: Taken together, we show that 18F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.

Keywords: PARP; PET; cancer; molecular imaging; olaparib.

MeSH terms

  • Animals
  • Boronic Acids / chemistry
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Copper / chemistry
  • Fluorine Radioisotopes*
  • Gene Expression Regulation, Enzymologic*
  • Mice
  • Mice, Inbred BALB C
  • Phthalazines* / chemistry
  • Piperazines* / chemistry
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Positron-Emission Tomography*
  • Radiochemistry
  • Tumor Hypoxia

Substances

  • Boronic Acids
  • Fluorine Radioisotopes
  • Phthalazines
  • Piperazines
  • Copper
  • Poly(ADP-ribose) Polymerases
  • Fluorine-18
  • olaparib