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

  • PDF / 509,763 Bytes
  • 9 Pages / 595.276 x 790.866 pts Page_size
  • 90 Downloads / 211 Views

DOWNLOAD

REPORT


RESEARCH ARTICLE

[18F]AZD2461, an Insight on Difference in PARP Binding Profiles for DNA Damage Response PET Imaging Florian Guibbal,1,2 Samantha L. Hopkins,1 Anna Pacelli,1 Patrick G. Isenegger,2 Michael Mosley,1 Julia Baguña Torres,1 Gemma M. Dias,1 Damien Mahaut,2 Rebekka Hueting,1 Véronique Gouverneur,2 Bart Cornelissen1 1

Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Old Road Campus Research Building , Off Roosevelt Drive, Oxford, OX3 7LJ, UK 2 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK

Abstract Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are extensively studied and used as anticancer 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, PANC1, 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. Key words: PET, AZD2461, PARP, Cancer, Molecular imaging

Florian Guibbal and Samantha L. Hopkins contributed equally to this work. Key Points Question: Can an isotopologue of the PARP inhibitor AZD2461 be used as an imaging agent of PARP expression in tumours in vivo? Pertinent findings: Selectivity of radiolabelled PARP inhibitors is important when evaluating tumour uptake. Implications for patient care: Careful consideration of selectivity patterns is needed when evaluating radiolabelled PARP inhibitors as pharmacokinetic and/or pharmacodynamic biomarker. Electronic supplementary material The online version of this article (https:// doi.org/10.1007/s11307-020-01497-6) contains supplementary material, which is available to authorized users. Correspondence to: Véronique Gouverneur; e-mail: [email protected], Bart Cornelissen; e-mail: [email protected]

Background Genomic instability in cancerous tissues is increased as a result