PET imaging of PARP expression using 68Ga-labelled inhibitors

Abstract

Purpose Imaging the PARP expression using 18F probes has been approved in clinical trials. Nevertheless, hepatobiliary clearance of both 18F probes hindered their application in monitoring abdominal lesions. Our novel 68Ga-labelled probes aim for fewer abdominal signals while ensuring PARP targeting by optimizing the pharmacokinetic properties of radioactive probes. Methods Three radioactive probes targeted PARP were designed, synthesized, and evaluated based on the PARP inhibitor Olaparib. These 68Ga-labelled radiotracers were assessed in vitro and in vivo. Results Precursors that did not lose binding affinity for PARP were designed, synthesized, and then labelled with 68Ga in high radiochemical purity (> 97%). The 68Ga-labelled radiotracers were stable. Due to the increased expression of PARP-1 in SK-OV-3 cells, the uptake of the three radiotracers by SK-OV-3 cells was significantly greater than that by A549 cells. PET/CT imaging of the SK-OV-3 models indicated that the tumor uptake of 68Ga-DOTA-Olaparib (0.5 h: 2.83 ± 0.55%ID/g; 1 h: 2.37 ± 0.64%ID/g) was significantly higher than that of the other 68Ga-labelled radiotracers. There was a significant difference in the T/M (tumor-to-muscle) ratios between the unblocked and blocked groups as calculated from the PET/CT images (4.07 ± 1.01 vs. 1.79 ± 0.45, P = 0.0238 < 0.05). Tumor autoradiography revealed high accumulation in tumor tissues, further confirming the above data. PARP-1 expression in the tumor was confirmed by immunochemistry. Conclusion As the first 68Ga-labelled PARP inhibitor, 68Ga-DOTA-Olaparib displayed high stability and quick PARP imaging in a tumor model. This compound is thus a promising imaging agent that can be used in a personalized PARP inhibitor treatment regimen.

Preclinical Evaluation and a Pilot Clinical Positron Emission Tomography Imaging Study of [68Ga]Ga-FAPI-FUSCC-II

“…At 0.5, 1, and 2 h post-injection, the mice were anesthetized and placed on an imaging bed for micro-PET/CT imaging. The blocking experiments were performed by coinjection with 500-fold excess of DOTA-FAPI-04 (250 μg/mouse) . Images were reconstructed using a three-dimensional ordered-subset expectation maximum algorithm based on the CT data for attenuation correction and converted to the percent injected dose per gram of tissue (% ID/g).…”

“…The mice injected with 1.85 MBq of [ 177 Lu]­Lu-FAPI-FUSCC-I or [ 177 Lu]­Lu-FAPI-FUSCC-II were sacrificed after anesthetization at 1, 6, and 24 h ( n = 3 for each point). Additionally, the mice that were coinjected with approximately 500-fold excess of DOTA-FAPI-04 (250 μg/mouse) were sacrificed at 1 h for the blocking study . All of the organs of interest and blood samples were collected and weighed, and the radioactivity was measured with a γ counter.…”

“…The blocking experiments were performed by coinjection with 500-fold excess of DOTA-FAPI-04 (250 μg/mouse). 21 Images were reconstructed using a three-dimensional ordered-subset expectation maximum algorithm based on the CT data for attenuation correction and converted to the percent injected dose per gram of tissue (% ID/g). Tumor-to-nontarget tissue (T/NT) ratio was calculated as the uptake of tumor divided by tumorcontralateral upper limb muscle.…”

“…Additionally, the mice that were coinjected with approximately 500-fold excess of DOTA-FAPI-04 (250 μg/mouse) were sacrificed at 1 h for the blocking study. 21 All of the organs of interest and blood samples were collected and weighed, and the radioactivity was measured with a γ counter. The data were normalized to % ID/g.…”

Design, Synthesis, and Evaluation of [18F]BIBD-300 as a Positron Emission Tomography Tracer for Poly(ADP-Ribose) Polymerase-1

“…12−14 Therefore, a series of tracers based on olaparib, rucaparib, niraparib, and talazoparib inhibitor structures have been developed, 15−18 [ 18 F]Olaparib, 20 [ 18 F]AZD2461, 21,22 [ 18 F]FTT, 23 [ 18 F]-Rucaparib, 24 [ 18 F]Talazoparib, 25 and [ 18 F]FPyPARP 17 (Figure 1), which provide important means for diagnosis, personalized planning, and efficacy evaluation. Among these PET tracers, [ 18 F]PARPi and [ 18 F]FTT are the most widely used in clinical practice. Although some current PARP-1 radiotracers have excellent tumor-to-background ratios, there is still room to improve the tumor-to-muscle ratio and reduce uptake in normal tissues such as muscle, bone, and liver.…”