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.

Highlights

  • Genomic instability in tumor tissue results from oncogenic and replicative stress, exogenous genotoxic insults, and tumorspecific DNA repair defects [1]

  • poly(ADPribose) polymerase (PARP) inhibitors reduce the enzymes’ catalytic activity by binding to their nicotinamide adenine dinucleotide binding pocket and interfere with the ability of the PARP-enzyme-inhibitor complex to dissociate from damaged DNA [3,4]

  • It has been reported that 30%–70% of patients with mutations in DNA damage repair machinery do not respond to therapies including PARP inhibitors [9]

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Summary

Introduction

Genomic instability in tumor tissue results from oncogenic and replicative stress, exogenous genotoxic insults, and tumorspecific DNA repair defects [1] Manipulating this genomic instability provides numerous therapeutic opportunities, and inhibitors of DNA damage repair enzymes have been explored as anticancer drugs [2]. Many tumors are known to be extremely Given these challenges, scientists have sought to use alternative methods to measure PARP expression in vivo, especially PARP-1. In 2015, Andersen et al reported an intricate 3-component carbonylation of aryl palladium species with the positron-emitting isotope 11C in the form of 11C-carbon monoxide [25] This gave the first direct, radiolabeled analog of olaparib, 11C-olaparib (Fig. 1, compound 7). 18F labeling would allow for a longer shelf life and results in intrinsically better spatial resolution

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