Scalable <sup>18</sup>F processing conditions for copper-mediated radiofluorination chemistry facilitate DoE optimization studies and afford an improved synthesis of [<sup>18</sup>F]olaparib

Bowden, Gregory D.; Chailanggar, Nantanat; Pichler, Bernd J.; Maurer, Andreas

doi:10.1039/d1ob00903f

Cited by 19 publications

(21 citation statements)

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“…We have previously explored the use of DoE to solve complex radiochemical optimization problems and have developed a workflow and 18 F processing method that is compatible with both small-scale DoE radiochemical experiments and large-scale automated tracer productions. 40 We applied this workflow to a computer-generated D-optimal DoE study designed to investigate the effects of precursor load (Pre, 5−30 μmol), copper-mediator load (Cop, 5−40 μmol), pyridine load (Py, 20−500 μmol), and concentration of n-BuOH co-solvent (Bu, 0−75%) in DMA, on the reaction performance (Figure 1A). The study consisted of 24 experiments (including centerpoints) and was conducted over 5 days (5 runs/day) using [ 18 F]fluoride from cyclotron target washes (Table S1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Given the short half-life of 18 F-fluorine (109.8 min), the synthesis of enantiomerically pure and isotopically radiolabeled [ 18 F]talazoparib represents a complex radiosynthetic challenge. An accessible radiosynthesis of [ 18 F]talazoparib has become possible because of the recent advances in radiochemical methodology research, such as the development of copper-mediated radiofluorination (CMRF) chemistry. − Our previous studies have explored this methodology by using the “design of experiments” (DoE) approach to reaction optimization, and this has helped us lay the foundation of a DoE-based radiotracer development pipeline using CMRF chemistry. , DoE aids in establishing reliable and robust radiosyntheses from the onset of the tracer development process and, in combination with the “de-risking” strategies described by Taylor et al , this approach can be used to expedite the development of novel radiotracers . In this work, we successfully applied a refined DoE-based tracer development workflow to the challenging radiosynthetic problem of [ 18 F]talazoparib.…”

Section: Introductionmentioning

confidence: 99%

“…35−38 Our previous studies have explored this methodology by using the "design of experiments" (DoE) approach to reaction optimization, and this has helped us lay the foundation of a DoE-based radiotracer development pipeline using CMRF chemistry. 39,40 DoE aids in establishing reliable and robust radiosyntheses from the onset of the tracer development process and, in combination with the "de-risking" strategies described by Taylor et al, this approach can be used to expedite the development of novel radiotracers. 41 In this work, we successfully applied a refined DoE-based tracer development workflow to the challenging radiosynthetic problem of [ 18 F]talazoparib.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2021

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Given the clinical potential of poly(ADP-ribose) polymerases (PARP) imaging for the detection and stratification of various cancers, the development of novel PARP imaging probes with improved pharmacological profiles over established PARP imaging agents is warranted. Here, we present a novel 18 F-labeled PARP radiotracer based on the clinically superior PARP inhibitor talazoparib. An automated radiosynthesis of [ 18 F]talazoparib (RCY: 13 ± 3.4%; n = 4) 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)-[ 18 F]Talazoparib demonstrated PARP binding in HCC1937 cells in vitro and showed an excellent tumor-to-blood ratio in xenograft-bearing mice (10.2 ± 1.5). Additionally, a favorable pharmacological profile in terms of excretion, metabolism, and target engagement was observed. This synthesis of [ 18 F]talazoparib exemplifies how DoE can enable the radiosyntheses of synthetically challenging radiolabeled compounds of high interest to the imaging community.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Meanwhile, Guibbal et al established procedures for automated radiosynthesis of [ 18 F]olaparib (120 min, activity yield: 6%), which are compatible with Eckert and Ziegler Modular Lab systems, offering promising perspectives for production for clinical studies and routine use [ 52 ]. Furthermore, Bowden et al was able to introduce a feasible automated copper-mediated radiofluorination, which led to an increase in activity yield (41%) and radiochemical yield (80%) [ 53 ]. Additional clinical and preclinical data obtained with [ 18 F]olaparib are eagerly awaited by the scientific community.…”

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

confidence: 99%

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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“…The first step featured a DoE optimized copper-mediated radiofluorination (CMRF) of either 4-(hydroxymethyl)phenylboronic acid pinacol ester or 3-(hydroxymethyl)phenylboronic acid to the respective paraor meta-fluorobenzyl alcohol. The [ 18 F]fluoride was processed to [ 18 F]TBAF in accordance to the previously published procedure [29]. The processed [ 18 F]TBAF was reacted with the relevant precursor (19 µmol) in the presence of Cu(OTf) 2 (5 µmol) and pyridine (25 µmol) in dimethyl acetamide (DMA) with n-BuOH (22%) as a co-solvent (total volume = 700 µL).…”

Section: [ 18 F]pfbg and [ 18 F]mfbg Synthesismentioning

confidence: 99%

Covalent 18F-Radiotracers for SNAPTag: A New Toolbox for Reporter Gene Imaging

et al. 2021

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There is a need for versatile in vivo nuclear imaging reporter systems to foster preclinical and clinical research. We explore the applicability of the SNAPTag and novel radiolabeled small-molecule ligands as a versatile reporter gene system for in vivo nuclear imaging. SNAPTag is a high-affinity protein tag used in a variety of biochemical research areas and based on the suicide DNA repair enzyme O6-methylguanine methyl transferase (MGMT). Its ligands are well suited for reporter gene imaging as the benzyl guanine core scaffold can be derivatized with fluorescent or radiolabeled moieties for various applications. Three guanine-based SNAPTag ligands ([18F]FBBG, [18F]pFBG and [18F]mFBG) were synthesized in high yields and were (radio)chemically characterized. HEK293 cells were engineered to express the SNAPTag on the cell surface and served as cell model to assess target affinity by radiotracer uptake assays, Western blotting and SDS-PAGE autoradiography. A subcutaneous HEK293-SNAPTag xenograft model in immunodeficient mice was used for in vivo evaluation of [18F]FBBG and [18F]pFBG while the biodistribution of [18F]mFBG was characterized in naïve animals. The results were validated by ex vivo biodistribution studies and immunofluorescence staining of the xenografts. All three radiotracers were produced in high radiochemical purity, molar activity and good yields. Western blot analysis revealed successful SNAPTag expression by the transfected HEK293 cells. In vitro testing revealed high target affinity of all three tracers with an up to 191-fold higher signal in the HEK293-SNAPTag cells compared to untransfected cells. This was further supported by a prominent radioactive protein band at the expected size in the SDS-PAGE autoradiograph of cells incubated with [18F]FBBG or [18F]pFBG. The in vivo studies demonstrated high uptake in HEK293-SNAP xenografts compared to HEK293 xenografts with excellent tumor-to-muscle ratios (7.5 ± 4.2 for [18F]FBBG and 10.6 ± 6.2 for [18F]pFBG). In contrast to [18F]pFBG and its chemical analogue [18F]mFBG, [18F]FBBG showed no signs of unspecific bone uptake and defluorination in vivo. Radiolabeled SNAPTag ligands bear great potential for clinical applications such as in vivo tracking of cell populations, antibody fragments and targeted radiotherapy. With excellent target affinity, good stability, and low non-specific binding, [18F]FBBG is a highly promising candidate for further preclinical evaluation.

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Scalable ¹⁸F processing conditions for copper-mediated radiofluorination chemistry facilitate DoE optimization studies and afford an improved synthesis of [¹⁸F]olaparib

Abstract: A convenient, scalable, and azeotropic drying free method for processing [18F]fluoride as base free [18F]TBAF is reported and applied to copper-mediated radiofluorination (CMRF) radiosyntheses. A central feature of this method...

Cited by 19 publications

References 28 publications

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

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

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

Covalent 18F-Radiotracers for SNAPTag: A New Toolbox for Reporter Gene Imaging

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Scalable 18F processing conditions for copper-mediated radiofluorination chemistry facilitate DoE optimization studies and afford an improved synthesis of [18F]olaparib

Abstract: A convenient, scalable, and azeotropic drying free method for processing [18F]fluoride as base free [18F]TBAF is reported and applied to copper-mediated radiofluorination (CMRF) radiosyntheses. A central feature of this method...

Cited by 19 publications

References 28 publications

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

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

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

Covalent 18F-Radiotracers for SNAPTag: A New Toolbox for Reporter Gene Imaging

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Scalable ¹⁸F processing conditions for copper-mediated radiofluorination chemistry facilitate DoE optimization studies and afford an improved synthesis of [¹⁸F]olaparib

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

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