Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ
Abstract Background Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PAR...
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SpringerOpen
2025-01-01
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| Series: | EJNMMI Radiopharmacy and Chemistry |
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| Online Access: | https://doi.org/10.1186/s41181-024-00323-6 |
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| author | Katarína Benčurová Theresa Balber Victoria Weissenböck Lukas Kogler Joachim Friske Verena Pichler Markus Mitterhauser Marcus Hacker Cécile Philippe Marius Ozenil |
| author_facet | Katarína Benčurová Theresa Balber Victoria Weissenböck Lukas Kogler Joachim Friske Verena Pichler Markus Mitterhauser Marcus Hacker Cécile Philippe Marius Ozenil |
| author_sort | Katarína Benčurová |
| collection | DOAJ |
| description | Abstract Background Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi. Results [carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection. Conclusions Although [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated. |
| format | Article |
| id | doaj-art-54f0aac9842a434297b855284ad0cc46 |
| institution | Kabale University |
| issn | 2365-421X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | SpringerOpen |
| record_format | Article |
| series | EJNMMI Radiopharmacy and Chemistry |
| spelling | doaj-art-54f0aac9842a434297b855284ad0cc462025-01-12T12:45:24ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2025-01-0110111510.1186/s41181-024-00323-6Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQKatarína Benčurová0Theresa Balber1Victoria Weissenböck2Lukas Kogler3Joachim Friske4Verena Pichler5Markus Mitterhauser6Marcus Hacker7Cécile Philippe8Marius Ozenil9Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaJoint Applied Medicinal Radiochemistry Facility, University of Vienna, Medical University of ViennaDivision of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaDivision of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaDivision of Molecular and Structural Preclinical Imaging, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaDivision of Pharmaceutical Chemistry, Department of Pharmaceutical Sciences, University of ViennaDivision of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaDivision of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaDivision of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaDivision of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of ViennaAbstract Background Poly (ADP-ribose) polymerase (PARP) enzymes are crucial for the repair of DNA single-strand breaks and have become key therapeutic targets in homologous recombination-deficient cancers, including prostate cancer. To enable non-invasive monitoring of PARP-1 expression, several PARP-1-targeting positron emission tomography (PET) tracers have been developed. Here, we aimed to preclinically investigate [carbonyl-11C]DPQ as an alternative PARP-1 PET tracer as it features a strongly distinct chemotype compared to the frontrunners [18F]FluorThanatrace and [18F]PARPi. Results [carbonyl-11C]DPQ was synthesised in a GE TracerLab FXC2 module, yielding sufficient activity (940 ± 410 MBq), molar activity (53 ± 16 GBq/µmol) and radiochemical purity (> 97%) for subsequent preclinical evaluation. [carbonyl-11C]DPQ showed high stability in formulation, in human plasma, and when incubated with human liver microsomes. In vitro, similar specific uptake was observed in both PC3 prostate cancer cells and CHO-K1 Chinese hamster ovary cells. However, in vivo studies using fertilised chicken eggs (in ovo model) revealed poor and non-displaceable tumour accumulation in PC3-derived xenografts, despite confirmed vascularisation and PARP-1 expression. Rapid uptake was observed in the liver (10 min), with less than 30% of the intact compound remaining in the liver 70 min post-injection. Conclusions Although [carbonyl-11C]DPQ demonstrated metabolic stability and specific binding in vitro, suboptimal tumour-targeting properties and pronounced liver metabolism were observed in ovo. Therefore, further animal experiments with mammalian models were not indicated.https://doi.org/10.1186/s41181-024-00323-6PARP-1DPQPETTracerC-11Preclinical evaluation |
| spellingShingle | Katarína Benčurová Theresa Balber Victoria Weissenböck Lukas Kogler Joachim Friske Verena Pichler Markus Mitterhauser Marcus Hacker Cécile Philippe Marius Ozenil Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ EJNMMI Radiopharmacy and Chemistry PARP-1 DPQ PET Tracer C-11 Preclinical evaluation |
| title | Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ |
| title_full | Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ |
| title_fullStr | Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ |
| title_full_unstemmed | Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ |
| title_short | Preclinical evaluation of the potential PARP-imaging probe [carbonyl-11C]DPQ |
| title_sort | preclinical evaluation of the potential parp imaging probe carbonyl 11c dpq |
| topic | PARP-1 DPQ PET Tracer C-11 Preclinical evaluation |
| url | https://doi.org/10.1186/s41181-024-00323-6 |
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