Discovery of Furanone-Based Radiopharmaceuticals for Diagnostic Targeting of COX-1 in Ovarian Cancer

Abstract

In vivo targeting and visualization of cyclooxygenase-1 (COX-1) using multimodal positron emission tomography/computed tomography imaging represents a unique opportunity for early detection and/or therapeutic evaluation of ovarian cancer because overexpression of COX-1 has been characterized as a pathologic hallmark of the initiation and progression of this disease. The furanone core is a common building block of many synthetic and natural products that exhibit a wide range of biological activities. We hypothesize that furanone-based COX-1 inhibitors can be designed as imaging agents for the early detection, delineation of tumor margin, and evaluation of treatment response of ovarian cancer. We report the discovery of 3-(4-fluorophenyl)-5,5-dimethyl-4-( p -tolyl)furan-2(5 H )-one (FDF), a furanone-based novel COX-1-selective inhibitor that exhibits adequate in vivo stability, plasma half-life, and pharmacokinetic properties for use as an imaging agent. We describe a novel synthetic scheme in which a Lewis acid-catalyzed nucleophilic aromatic deiodo[ 18 F]fluorination reaction is utilized for the radiosynthesis of [ 18 F]FDF. [ 18 F]FDF binds efficiently to COX-1 in vivo and enables sensitive detection of ovarian cancer in subcutaneous and peritoneal xenograft models in mice. These results provide the proof of principle for COX-1-targeted imaging of ovarian cancer and identify [ 18 F]FDF as a promising lead compound for further preclinical and clinical development.

Repurposing 11C-PS13 for PET Imaging of Cyclooxygenase-1 in Ovarian Cancer Xenograft Mouse Models

“…3C). Our study demonstrated a 3-fold greater tumor accumulation with [ 11 C]PS13 than that reported for [ 18 F]FDF in a s.c. OvCa xenograft mouse model (14). We also demonstrated the potential of [ 11 C]PS13 to detect early stage OvCa in clinically relevant i.p.…”

“…OVCAR-3 human OvCa cells (American Type Culture Collection) with high COX-1 expression (14) were cultured in RPMI 1640 medium supplemented with 20% fetal bovine serum (Gibco, Life Technologies), 1% penicillin/streptomycin (Sigma-Aldrich), and 0.01 mg/mL bovine insulin (Sigma-Aldrich). Cells were cultured in an atmosphere of 5% CO2 at 37°C.…”

Fluorochrome Selection for Imaging Intraoperative Ovarian Cancer Probes

“…Novel compounds have been designed to target the COX-1 [12], especially in tumor cells and tissues where it is overexpressed [13][14][15][16][17]. From a chemical viewpoint, the molecules must carry at least three moieties: a mofezolac unit recognized through its carboxylic group by COX amino acid residues (Arg120, Tyr355, and Glu524) located at the entrance of the enzyme long hydrophobic channel that has the catalytic site on its top [18], a linker and a fluorochrome.…”

“…The synthesis of 17a-b started with the conversion of 6-bromo-2-propyl-1H-benzo[de] isoquinoline-1,3(2H)-dione ( 14) into its N-propyl imide (15); in turn, reacting with 1,6hexanediamine or 1,4-phenylenediamine afforded 16a-b intermediates. The latter, in the presence of the coupling reagent and mofezolac, provided the two products 17a-b (Scheme 5).…”

Fluorine-18 Labelled Radioligands for PET Imaging of Cyclooxygenase-2

“…Therefore, in addition to non-selective classical non-steroidal anti-inflammatory drugs (NSAIDs: acetylsalicylic acid, ibuprofen, flurbiprofen, naproxen, indomethacin, diclofenac, mefenamic acid, piroxicam, etc. ), recently, COX-1-selective inhibitors [11,24], fluorescence imaging probes [25][26][27][28] and PET radioligands [25,26,[29][30][31][32] gem-difluorovinyl precursors [33]. Despite low molar activity, the [ 18 F]PS13 radioligand was evaluated for COX-1 PET imaging in monkeys.…”