[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

Guibbal, Florian; Hopkins, Samantha L.; Pacelli, Anna; Isenegger, Patrick G.; Mosley, Michael; Torres, Júlia Baguña; Dias, Gemma; Mahaut, Damien; Hueting, Rebekka; Gouverneur, Véronique; Cornelissen, Bart

doi:10.1007/s11307-020-01497-6

Cited by 13 publications

(20 citation statements)

References 35 publications

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“…Almost in parallel, a radiofluorinated isotopologue of AZD2461 was synthesized via copper-mediated 18 F-fluorodeboronation (Gouverneur and Cornelissen lab). [ 18 F]AZD2461 was evaluated in pancreatic cancer cell lines and a xenograft mouse model of pancreatic cancer in comparison to [ 18 F]olaparib, which was developed in the same lab [56]. Cellular uptake of [ 18 F]AZD2461 in PSN-1 cells was less than 50% compared to the [ 18 F]olaparib.…”

Section: Olaparib-like Radiotracersmentioning

confidence: 99%

“…Finally, the most likely source of microbiological contamination in a GMP laboratory is a human operator; thus, limiting manual intervention reduces the risk of contaminating the final product [108]. For some of the PARP radiopharmaceuticals discussed in this review, namely the BODIPY analogue of [ 18 F]PARPi, [ 18 F]PARPi-FL, the 18 F-fluoroethyl analogue of AZD2461, the 18 F-fluorethyl version of rucaparib, [ 18 F]SuPAR, [ 18 F]olaparib, and [ 18 F]AZD2461, an automated procedure was already published [34,52,55,56,66,74]. For many, however, only a manual radiosynthesis was performed, and in some cases the reported procedures might be difficult to perform on an automated platform.…”

Section: Considerations For Clinical Manufacturingmentioning

confidence: 99%

“…Radiosynthesis scale-up, especially of radiopharmaceuticals made with short-lived isotopes, has several benefits, including increased final dose, and therefore is able to scan more than one patient with a single synthesis and transfer of doses to centers at certain distances from the production site. For instance, while the starting activity of manually synthesized 18 F PET tracers herein reviewed was reported, it was, in most cases, in the 500-1800 MBq range, and it could be increased to 20-30 GBq for some automated syntheses [55,56]. However, there are also certain challenges involved in scaling-up radiosynthesis.…”

Section: Considerations For Clinical Manufacturingmentioning

confidence: 99%

“…Interestingly, blocking with olaparib or AZD2461 only reduced the [ 18 F]AZD2461 uptake to 70% and 25% of the initial binding, respectively, while both olaparib and AZD2461, could completely block [ 18 F]olaparib uptake. In vivo, [ 18 F]AZD2461 uptake could also not be blocked completely, but curiously olaparib was more efficient at blocking than AZD2461 [ 56 ]. These results could suggest that AZD2461 has other, currently unknown, targets in addition to PARP1 and PARP2 and is hence less suitable as a PARP imaging agent.…”

Section: Preclinical Development and Recent Advances In Parp Imaging ...mentioning

confidence: 99%

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DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Nguyen

Pacelli

Nader

et al. 2022

Cancers

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Since it was discovered that many tumor types are vulnerable to inhibition of the DNA repair machinery, research towards efficient and selective inhibitors has accelerated. Amongst other enzymes, poly(ADP-ribose)-polymerase 1 (PARP1) was identified as a key player in this process, which resulted in the development of selective PARP inhibitors (PARPi) as anti-cancer drugs. Most small molecule PARPi’s exhibit high affinity for both PARP1 and PARP2. PARPi are under clinical investigation for mono- and combination therapy in several cancer types and five PARPi are now clinically approved. In parallel, radiolabeled PARPi have emerged for non-invasive imaging of PARP1 expression. PARP imaging agents have been suggested as companion diagnostics, patient selection, and treatment monitoring tools to improve the outcome of PARPi therapy, but also as stand-alone diagnostics. We give a comprehensive overview over the preclinical development of PARP imaging agents, which are mostly based on the PARPi olaparib, rucaparib, and recently also talazoparib. We also report on the current status of clinical translation, which involves a growing number of early phase trials. Additionally, this work provides an insight into promising approaches of PARP-targeted radiotherapy based on Auger and α-emitting isotopes. Furthermore, the review covers synthetic strategies for PARP-targeted imaging and therapy agents that are compatible with large scale production and clinical translation.

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Section: Olaparib-like Radiotracersmentioning

confidence: 99%

Section: Considerations For Clinical Manufacturingmentioning

confidence: 99%

Section: Considerations For Clinical Manufacturingmentioning

confidence: 99%

Section: Preclinical Development and Recent Advances In Parp Imaging ...mentioning

confidence: 99%

See 2 more Smart Citations

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

Nguyen

Pacelli

Nader

et al. 2022

Cancers

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“…The Reiner group showed, for example, that altering the iodination position on the aromatic ring and the length of the linker between the iodinated-aromatic ring and the olaparib core resulted in very different IC50 values for PARP-1 (57). Similarly, recently reported on the effects of structure modification on tumor uptake and target specificity of the olaparib-derived radiolabeled PARPi [ 18 F]olaparib and [ 18 F]AZD2461 (70).…”

Section: Radiolabeled Parp Inhibitors: Imaging and Therapymentioning

confidence: 99%

PARP Inhibitors in Cancer Diagnosis and Therapy

Chan

Tan

Cornelissen

2020

Clinical Cancer Research

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Targeting of poly(ADP-ribose)polymerase (PARP) enzymes has emerged as an effective therapeutic strategy to selectively target cancer cells with deficiencies in homologous recombination (HR) signaling. Currently used to treat BRCA-mutated cancers, PARP inhibitors (PARPi) have demonstrated improved outcome in various cancer types as single agents. Ongoing efforts have seen the exploitation of PARPi combination therapies, boosting patient responses as a result of drug synergisms.Despite great successes using PARPi therapy, selecting those patients who will benefit from single agent or combination therapy remains one of the major challenges.Numerous reports have demonstrated that the presence of a BRCA mutation does not always result in synthetic lethality with PARPi therapy in treatment-naïve tumors.Cancer cells can also develop resistance to PARPi therapy. Hence, combination therapy may significantly affect the treatment outcomes. In this review, we discuss the development and utilization of PARPi in different cancer types from preclinical models to clinical trials, provide a current overview of the potential uses of PARP imaging agents in cancer therapy, and discuss the use of radiolabeled PARPi as radionuclide therapies.

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Imaging PARP with [18F]rucaparib in pancreatic cancer models

Chan

Chen

Destro

et al. 2022

Eur J Nucl Med Mol Imaging

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Purpose Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models. Method We incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. Results Uptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. Conclusion Taken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.

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[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging

Cited by 13 publications

References 35 publications

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

DNA Repair Enzyme Poly(ADP-Ribose) Polymerase 1/2 (PARP1/2)-Targeted Nuclear Imaging and Radiotherapy

PARP Inhibitors in Cancer Diagnosis and Therapy

Imaging PARP with [18F]rucaparib in pancreatic cancer models

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