Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [18F]olaparib

Guibbal, Florian; Isenegger, Patrick G.; Wilson, Thomas C.; Pacelli, Anna; Mahaut, Damien; Sap, Jeroen B. I.; Taylor, Nicholas J.; Verhoog, Stefan; Preshlock, Sean; Hueting, Rebekka; Cornelissen, Bart; Gouverneur, Véronique

doi:10.1038/s41596-020-0295-7

Cited by 43 publications

(47 citation statements)

References 41 publications

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“…Gouverneur reported the application of this method to clinically relevant tracers including 3-[ 18 (Taylor et al 2017) as well as an extensive study providing radiochemists with guidelines on how to apply this radiochemistry to label complex drug candidates featuring multiple functionalities including nitrogen-containing heterocycles and heteroarenes. (Guibbal et al 2020) More recently, Gouverneur also reported the automated radiosynthesis of [ 18 F] (Sharninghausen et al 2020) N-heterocyclic carbene (NHC) Cu-complexes were investigated by Sanford and Scott for the ligand-directed radiofluorination of aryl halides (Ar-X, X = Br, Cl, I); the narrow substrate scope and the need of rigorous air-free and anhydrous conditions limit the applicability of this methodology (Fig. 5C) (Xu et al 2021).…”

Section: Iii122 Coppermentioning

confidence: 99%

Closing the gap between 19F and 18F chemistry

Ajenjo

Destro

Cornelissen

et al. 2021

EJNMMI radiopharm. chem.

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Positron emission tomography (PET) has become an invaluable tool for drug discovery and diagnosis. The positron-emitting radionuclide fluorine-18 is frequently used in PET radiopharmaceuticals due to its advantageous characteristics; hence, methods streamlining access to 18F-labelled radiotracers can make a direct impact in medicine. For many years, access to 18F-labelled radiotracers was limited by the paucity of methodologies available, and the poor diversity of precursors amenable to 18F-incorporation. During the last two decades, 18F-radiochemistry has progressed at a fast pace with the appearance of numerous methodologies for late-stage 18F-incorporation onto complex molecules from a range of readily available precursors including those that do not require pre-functionalisation. Key to these advances is the inclusion of new activation modes to facilitate 18F-incorporation. Specifically, new advances in late-stage 19F-fluorination under transition metal catalysis, photoredox catalysis, and organocatalysis combined with the availability of novel 18F-labelled fluorination reagents have enabled the invention of novel processes for 18F-incorporation onto complex (bio)molecules. This review describes these major breakthroughs with a focus on methodologies for C–18F bond formation. This reinvigorated interest in 18F-radiochemistry that we have witnessed in recent years has made a direct impact on 19F-chemistry with many laboratories refocusing their efforts on the development of methods using nucleophilic fluoride instead of fluorination reagents derived from molecular fluorine gas.

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Section: Iii122 Coppermentioning

confidence: 99%

Closing the gap between 19F and 18F chemistry

Ajenjo

Destro

Cornelissen

et al. 2021

EJNMMI radiopharm. chem.

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“…A protecting group strategy using the trimethylsilylethoxymethyl (SEM) ether protecting group was successfully employed by Wilson et al for the "de-risked" radiosynthesis of [ 18 F]olaparib, a PARP tracer structurally related to talazoparib. 40,[43][44] We thus applied the same protecting group strategy to compounds 5a and 5b, which were protected with SEM-Cl using sodium hydride in DMF at 0 °C. These conditions afforded both the mono-(6a) and di-SEM (6b) protected bromide derivatives in an approximate 2:1 ratio.…”

Section: Scheme 1: Synthesis Of Advanced Intermediates For [ 18 F]talazoparib Precursor Synthesismentioning

confidence: 99%

DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer.

Bowden¹,

Stotz²,

Kinzler³

et al. 2021

Preprint

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PARP inhibitors are proven chemotherapeutics and serve as lead structures for the development of PARP-targeted in vivo imaging probes. Given the clinical potential of PARP imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacologi-cal profiles over established PARP imaging agents is warranted. Here, we present a novel 18F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [18F]talazoparib (RCY: 13 ± 3.4 %; n = 4; molar radioactivity 52 – 176 GBq/μmol) was achieved using a “Design of Experiments” (DoE) optimized copper-mediated radiofluorination reaction. The chiral product was isolated from the reaction mixture using 2D reversed-phase/chiral radio-HPLC (>99% ee). (8S, 9R)-[18F]Talazoparib demonstrated PARP binding in HCC1937 cells in vitro and showed an excellent tumor-to-blood ratio in xeno-graft-bearing mice (10.2 ± 1.5). Despite expected uptake into muscle, bone, and abdominal tissue, a favorable pharmacological profile in terms of excretion, blood half-life, and target engagement was observed in the pilot in vivo study. This synthesis of [18F]talazoparib exemplifies how a DoE based tracer development pipeline can enable the radiosyntheses of clinically relevant but synthetically challenging radiolabeled compounds of high interest to the imaging community.

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“…1 and 2). [ 18 F]AZD2461 was also obtained via a fully automated method, using a previously described procedure, and then applied for [ 18 F]olaparib [28]. See Supplemental Information for a full description of both radiosyntheses.…”

Section: Synthesismentioning

confidence: 99%

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

et al. 2020

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Background Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anti-cancer drugs, as single agents or in combination with other therapies. Most radiotracers developed to date have been chosen on the basis of strong PARP1–3 affinity. Herein, we propose to study AZD2461, a PARP inhibitor with lower affinity towards PARP3, and to investigate its potential for PARP targeting in vivo. Methods Using the Cu-mediated 18F-fluorodeboronation of a carefully designed radiolabelling precursor, we accessed the 18F-labelled isotopologue of the PARP inhibitor AZD2461. Cell uptake of [18F]AZD2461 in vitro was assessed in a range of pancreatic cell lines (PSN-1, PANC-1, CFPAC-1 and AsPC-1) to assess PARP expression and in vivo in xenograft-bearing mice. Blocking experiments were performed with both olaparib and AZD2461. Results [18F]AZD2461 was efficiently radiolabelled via both manual and automated procedures (9 % ± 3 % and 3 % ± 1 % activity yields non-decay corrected). [18F]AZD2461 was taken up in vivo in PARP1-expressing tumours, and the highest uptake was observed for PSN-1 cells (7.34 ± 1.16 %ID/g). In vitro blocking experiments showed a lesser ability of olaparib to reduce [18F]AZD2461 binding, indicating a difference in selectivity between olaparib and AZD2461. Conclusion Taken together, we show the importance of screening the PARP selectivity profile of radiolabelled PARP inhibitors for use as PET imaging agents.

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Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [18F]olaparib

Cited by 43 publications

References 41 publications

Closing the gap between 19F and 18F chemistry

Closing the gap between 19F and 18F chemistry

DoE Optimization Empowers the Automated Preparation of Enantiomerically Pure [18F]Talazoparib and its In Vivo Evaluation as a PARP Radiotracer.

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

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