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

Abstract

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol.

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Fig. 1
Fig. 2: Chromatograms of semi-preparative radio-HPLC of [18F]olaparib purification.
Fig. 3: General setup for the automated synthesis of [18F]olaparib.
Fig. 4
Fig. 5

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Acknowledgements

We acknowledge financial support from the Medical Research Council (MRC MR/R01695X/1, F.G. and A.P.), the Engineering and Physical Sciences Research Council (EPSRC EP/N509711/1, EP/L025604/1, J.B.I.S. and S.P.) and the Biotechnology and Biological Sciences Research Council (BBSRC BB/ K01191X/1; N.J.T. and P.G.I.). This work was also supported by the Cancer Research UK (CRUK C5255/A16466, T.C.W. and S.V.), Pfizer, UCB, and the Swiss National Science Foundation (P2BSP2_178609, P.G.I.). We thank T. C. Wilson for providing the copper complex.

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Authors

Contributions

B.C. and V.G. conceived and designed this research. F.G., P.G.I., T.C.W., A.P., D.M., J.B.I.S., N.J.T., S.V., S.P. and R.H. performed the experimental work. All authors analyzed the data and wrote the manuscript.

Corresponding authors

Correspondence to Bart Cornelissen or Véronique Gouverneur.

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The authors declare no competing interests.

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Peer review information Nature Protocols thanks Ralf Schirrmacher and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Key references using this protocol

Preshlock, S., Tredwell, M. & Gouverneur, V. Chem. Rev. 116, 719–766 (2016): https://pubs.acs.org/doi/abs/10.1021/acs.chemrev.5b00493

Wilson, T. C. et al. J. Nucl. Med. 60, 504–510 (2019): http://jnm.snmjournals.org/content/60/4/504.full

Taylor, N. J. et al. J. Am. Chem. Soc. 139, 8267–8276 (2017): https://pubs.acs.org/doi/abs/10.1021/jacs.7b03131

Key data used in this protocol

Wilson, T. C. et al. J. Nucl. Med. 60, 504–510 (2019): http://jnm.snmjournals.org/content/60/4/504.full

Integrated supplementary information

Supplementary Figure 1 Purified [18F]olaparib was injected onto an analytical column for quality control analysis.

Radiotrace A, UV trace B. A sample spiked with an authentic reference sample of olaparib (0.7 µg) was analysed (C).Analytical HPLC conditions: SynergiTM (4 µm Hydro-RP 80Å LC column 150 x 4.6 mm) column with 25% MeCN and 75% water (vol/vol) using a flow rate of 1 mL/min. This figure was originally published in Wilson, T. C. et al. PET Imaging of PARP Expression Using 18F-Olaparib. J. Nucl. Med. 60, 504–510, © 2019 Society of Nuclear Medicine and Molecular Imaging.

Supplementary Figure 2 HPLC UV trace of 4-(3-(4-(cyclopropanecabonyl)piperazine-1-carbnonyl)benzyl)phthalazin-1(2H)-one and olaparib.

HPLC Eluent: Synergi 4 µm Hydro-RP 80A, 150 x 4.6 mm with 25% MeCN/75% H2O (isocratic 1 mL/min (vol/vol)) monitoring with UV (220 nm). This figure was originally published in Wilson, T. C. et al. PET Imaging of PARP Expression Using 18F-Olaparib. J. Nucl. Med. 60, 504–510, © 2019 Society of Nuclear Medicine and Molecular Imaging. 18F-Fluorodeboronation of 10 may lead to the formation of proto-deborylated side-product. As a result, we have developed an HPLC method allowing clean separation of olaparib from this side-product.

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Supplementary Figs. 1 and 2 and Supplementary Methods 1–3.

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Guibbal, F., Isenegger, P.G., Wilson, T.C. et al. Manual and automated Cu-mediated radiosynthesis of the PARP inhibitor [18F]olaparib. Nat Protoc 15, 1525–1541 (2020). https://doi.org/10.1038/s41596-020-0295-7

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