Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [18F]olaparib in mouse models of glioma

Chung Ying Chan; Samantha L Hopkins; Florian Guibbal; Anna Pacelli; Julia Baguña Torres; Michael Mosley; Doreen Lau; Patrick Isenegger; Zijun Chen; Thomas C Wilson; Gemma Dias; Rebekka Hueting; Véronique Gouverneur; Bart Cornelissen

doi:10.1186/s13550-022-00940-9

Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [¹⁸F]olaparib in mouse models of glioma

EJNMMI Res. 2022 Oct 9;12(1):67. doi: 10.1186/s13550-022-00940-9.

Authors

Affiliations

¹ CRUK/MRC Oxford Institute for Radiation Oncology, Department of 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, South Parks Road, Oxford, OX1 3TA, UK.
³ Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, South Parks Road, Oxford, OX1 3TA, UK. veronique.gouverneur@chem.ox.ac.uk.
⁴ CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7LJ, UK. bart.cornelissen@oncology.ox.ac.uk.
⁵ Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. bart.cornelissen@oncology.ox.ac.uk.

^# Contributed equally.

Abstract

Purpose: Radiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [¹⁸F]olaparib and the injected mass of [^TotalF]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models.

Methods: [¹⁸F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [^TotalF]olaparib (varying injected mass: 0.04-8.0 µg, and molar activity: 1-320 GBq/μmol).

Results: Selective uptake of [¹⁸F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [^TotalF]olaparib (µg) but not the molar activity. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [^TotalF]olaparib resulted in lower relative tumour uptake (%ID/g; P < 0.05). Ex vivo analysis of U87MG xenograft sections showed that the heterogeneity in [¹⁸F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [^TotalF]olaparib (> 0.5 µg).

Conclusion: Our findings show that the injected mass of [^TotalF]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.

Keywords: Glioblastoma; Olaparib; PARP; PET; [18F]olaparib.

Abstract

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