Abstract
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Objectives: Poly (ADP-ribose) polymerase-1 (PARP-1) has been pursued as a promising therapeutic target for the treatment of cancer. Due to the important roles of PARP-1 in cancer biology, positron emission tomography (PET) imaging agents have been developed. Several showed potential for imaging PARP-1 expression in breast cancer and brain cancer in small animals. PARP-1 also plays many roles in prostate cancer (PC); recent preclinical and clinical data suggest that men with certain mutations in DNA repair pathways in PC can derive therapeutic benefit from PARP inhibition therapy. Although no evaluation of PARP-1 PET imaging agents in PC has yet been reported, our preliminary data indicates the reported PARP-1 imaging agents may not ideal for this purpose because of high, blockable uptake in normal prostate and in healthy bone. Our objectives are to synthesize and evaluate a novel PARP-1 ligands for PET imaging of PARP-1 expression in PC.
Methods: [18F]WC-DZ-F (Ki = 6 nM), a derivative of PARP-1 radioligands [18F]FluorThanatrace and [125I]KX1, was synthesized by a two-step method, starting from [18F]fluorobenzaldehyde. In vitro uptake of [18F]WC-DZ-F was evaluated in PC-3 cells with olaparib as the blocking agent. MicroPET imaging of [18F]WC-DZ-F was evaluated in nu/nu mice with PC-3 xenograft tumors using olaparib as the blocking or displacing agent, and ex vivo autoradiography of PC-3 tumors was carried out after microPET imaging. Biodistribution of [18F]WC-DZ-F was carried out in non-tumor bearing nu/nu male mice.
Results: [18F]WC-DZ-F was synthesized in good yield with high chemical and radiochemical purity, and high specific activity. Cell uptake indicates high (up to 5 fold) and PARP-1 specific uptake of [18F]WC-DZ-F in PC-3 cells. In the microPET imaging study, [18F]WC-DZ-F accumulated in PC-3 tumors over 2 hours, and the uptake was significantly reduced by blocking experiment with olaparib. PC-3 tumors are clearly visualized in microPET images. The imaging results were further confirmed by the autoradiograph of PC-3 tumors ex vivo. In the biodistribution study, except for liver, which appears to be the metabolism site, [18F]WC-DZ-F washed out quickly from most organs/tissues over 2 hours, including spleen, kidney and pancreas. The uptake in prostate is low (0.25±0.11 %ID/dose), and the uptake in bone is moderate (1.27±0.11 %ID/dose), and was not blockable by olaparib (1.31±0.19 %ID/dose).
Conclusions: We synthesized a novel PARP-1 radioligand, [18F]WC-DZ-F and demonstrated its potential in PET imaging of PARP-1 expression in the PC-3 model of PC by in vitro cell uptake studies, microPET imaging and postPET autoradiography, and biodistribution in normal mice. Further evaluation in other models of PC are warranted. Research Support: NIH: CA25836