Imaging PARP with [18F]rucaparib in pancreatic cancer models

Abstract

Purpose Rucaparib, an FDA-approved PARP inhibitor, is used as a single agent in maintenance therapy to provide promising treatment efficacy with an acceptable safety profile in various types of BRCA-mutated cancers. However, not all patients receive the same benefit from rucaparib-maintenance therapy. A predictive biomarker to help with patient selection for rucaparib treatment and predict clinical benefit is therefore warranted. With this aim, we developed [18F]rucaparib, an 18F-labelled isotopologue of rucaparib, and employed it as a PARP-targeting agent for cancer imaging with PET. Here, we report the in vitro and in vivo evaluation of [18F]rucaparib in human pancreatic cancer models. Method We incorporated the positron-emitting 18F isotope into rucaparib, enabling its use as a PET imaging agent. [18F]rucaparib binds to the DNA damage repair enzyme, PARP, allowing direct visualisation and measurement of PARP in cancerous models before and after PARP inhibition or other genotoxic cancer therapies, providing critical information for cancer diagnosis and therapy. Proof-of-concept evaluations were determined in pancreatic cancer models. Results Uptake of [18F]rucaparib was found to be mainly dependent on PARP1 expression. Induction of DNA damage increased PARP expression, thereby increasing uptake of [18F]rucaparib. In vivo studies revealed relatively fast blood clearance of [18F]rucaparib in PSN1 tumour-bearing mice, with a tumour uptake of 5.5 ± 0.5%ID/g (1 h after i.v. administration). In vitro and in vivo studies showed significant reduction of [18F]rucaparib uptake by addition of different PARP inhibitors, indicating PARP-selective binding. Conclusion Taken together, we demonstrate the potential of [18F]rucaparib as a non-invasive PARP-targeting imaging agent for pancreatic cancers.

A radioiodinated rucaparib analogue as an Auger electron emitter for cancer therapy.

“…Consistent with previously reported data [24], an increased concentration of radiotracer given to cancer cells resulted in increased cell uptake of radioactive material as shown in Fig. 3B.…”

“…Western blot revealed that expression of PARP-1 was higher in PSN-1 and FLO-1 cells than others, consistent with previously reported data [24], while expression of PARP-2 was higher in OE-33 and H1299 (Fig. 3G).…”

“…1). Our group recently reported the radiosynthesis of [ 18 F]olaparib [21], [ 18 F]AZD2461 [22] and [ 18 F]rucaparib [23,24], demonstrating the strength of copper mediated radiofluorination as a useful methodology to overcome the challenge of C-18 F bond formation [25,26] and that radiolabelled versions of PARP inhibitors can prove to be useful PET imaging agents. [27][28] Here, we present the synthesis, radiosynthesis and preclinical evaluation of iodine-123 labelled rucaparib analogue, 8-[ 123 I]iodo-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino [5,4,3cd]indol-1-one, [ 123 I]GD1, as a potential radiotracer for RLT, via copper mediated radioiodination building on our previous work with [ 18 F]rucaparib.…”

“…[27][28] Here, we present the synthesis, radiosynthesis and preclinical evaluation of iodine-123 labelled rucaparib analogue, 8-[ 123 I]iodo-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino [5,4,3cd]indol-1-one, [ 123 I]GD1, as a potential radiotracer for RLT, via copper mediated radioiodination building on our previous work with [ 18 F]rucaparib. [23,24] Fig. 1: Olaparib-and Rucaparib-based PARP-targeted RLT agents.…”

“…4: In vivo studies evaluating [ 123 I]GD1 biodistribution in wild type mice. A) Biodistribution of [ 123 I]GD1 in selected tissues in wildtype mice, 2 or 24 h after intravenous administration of [ 123 I]GD1 (1.3 MBq, 7GBq/μmol), compared to [ 18 F]rucaparib[24].B) SPECT/CT scan images, following intravenous…”