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]
Summary
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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