Synthesis, [18F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography

Abstract

Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be 18F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50 = 6.3 nM). [18F]12 was synthesized under conventional conditions in high specific activity with 40-50 % decay-corrected yield. MicroPET studies using [18F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [18F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [18F]12 in the tumor is specific to PARP-1 expression.

Molecular Imaging of PARP

“…AG14361-which has been shown to be specific to PARP1 (32)-and its derived radiotracers feature a benzimidazole instead of rucaparib's fluorinated indole. 18 F-FluorThanatrace ( 18 F-FTT) (23,(33)(34)(35) (IC 50 , 6.3 nM), which replaces dimethyl phenylmethanamine on AG14361 with 18 F-fluoroethoxy benzene, was first tested in MDA-MB-436 and MDA-MB-231 xenografts. PET imaging showed 3-5 %ID/g tumor uptake after 60 min, which was reduced to 2 %ID/g after olaparib blocking.…”

PARP-1 Expression Quantified by [18F]FluorThanatrace: A Biomarker of Response to PARP Inhibition Adjuvant to Radiation Therapy

“…Radiosynthesis was done in accordance with current Good Manufacturing Practices (cGMP) for PET radiopharmaceuticals. 23 …”

“…21 We have previously shown that these radiotracers bind to PARP in vivo by using breast cancer tumor models and can be competitively blocked by using a clinical PARP inhibitor. 22,23 In this study, we explored a PARP-1 PET imaging agent [ The cell lines used in this study were selected based on the genetic profile as either ovarian cancer BRCA1 mutant (SNU-251) or BRCA1 functional-wild type (SKOV3). We hypothesize that [ 18 F]FTT uptake in vitro will correspond to PARP-1 expression, and ovarian cancer cells with higher PARP-1 expression will be more sensitive to PARP inhibition adjuvant to radiation therapy.…”

Novel Strategies for Breast Cancer Imaging: New Imaging Agents to Guide Treatment

“…The low specific activity of 18 F-PARPi-Fl, which is radiolabeled with 18 F for 19 F exchange, likely will limit the clinical utility of this probe. 18 F-fluorthanatrace showed high uptake in a breast tumor with a high level of expression of PARP1; this uptake could be blocked with olaparib, suggesting that this uptake was specific to PARP1 expression (52). A phase 0 clinical trial of 18 F-fluorthanatrace is currently being conducted at Washington University, and new trials on other tumor types and in various therapeutic settings are planned.…”