Synthesis and Evaluation of the Estrogen Receptor β–Selective Radioligand 2-¹⁸F-Fluoro-6-(6-Hydroxynaphthalen-2-yl)Pyridin-3-ol: Comparison with 16α-¹⁸F-Fluoro-17β-Estradiol

Abstract

Estrogen receptors (ERs) are targets for endocrine treatment of estrogen-dependent cancers. The ER consists of 2 isoforms, ERα and ERβ, which have distinct biologic functions. Whereas activation of ERα stimulates cell proliferation and cell survival, ERβ promotes apoptosis. PET of ERα and ERβ levels could provide more insight in response to hormonal treatment. 16α-F-fluoro-17β-estradiol (F-FES) is a PET tracer for ER with relative selectivity for ERα. Here we report the synthesis and evaluation of a potential ERβ-selective PET tracer: 2-F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (F-FHNP). F-FHNP was synthesized by fluorination of the corresponding nitro precursor, followed by acidic removal of the 2-methoxyethoxymethyl protecting group. In vitro affinity ofF-FHNP and F-FES for ER was evaluated in SKOV3 ovarian carcinoma cells. PET imaging and ex vivo biodistribution studies withF-FHNP and F-FES were conducted in athymic nude mice bearing a SKOV3 xenografts.F-FHNP had nanomolar affinity for ERs, with a 3.5 times higher affinity for ERβ. F-FHNP was obtained in 15%-40% radiochemical yield (decay-corrected), with a specific activity of 279 ± 75 GBq/μmol.F-FHNP had a dissociation constant of 2 nM and maximum binding capacity of 18 fmol/10 cells, and F-FES had a dissociation constant of 3 nM and maximum binding capacity 83 fmol/10 SKOV3 cells. Both F-FHNP andF-FES PET could clearly visualize the tumor in male mice bearing a SKOV3 xenograft. Biodistribution studies showed similar distribution of F-FHNP andF-FES in most peripheral organs. F-FES showed a 2-fold-higher tumor uptake thanF-FHNP. The tumor-to-plasma ratio of F-FES decreased 55% ( = 0.024) and 8% ( = 0.68) when administered in the presence of estradiol (nonselective) and genistein (ERβ-selective), respectively. The tumor-to-plasma ratio of F-FHNP decreased 41% ( = 0.004) and 64% ( = 0.0009) when administered with estradiol and genistein, respectively. The new PET tracerF-FHNP has suitable properties for imaging and shows relative selectivity for ERβ.

Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET

“…In our preclinical study, [ 18 F]FES uptake in SKOV3 xenografts (SUV max 0.21-0.27) was relatively low when compared with tracer uptake in the breast or ovarian cancer in patients (SUV 1.5-6.0) [15,16]. Such low [ 18 F]FES uptake was also observed in other preclinical studies in tumor-bearing mice [17,18]. A plausible cause for the low uptake of [ 18 F]FES in this study is the relatively low expression of ER in the SKOV3 tumor cell line (ca.…”

“…830 fmol/mg of protein) compared with, for example, the frequently used ER-expressing MCF7 breast tumor cell line (ca. 1900 fmol/mg of protein) [18,19].…”

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

“…The most common PET radiopharmaceutical for OvCa, 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG), has downfalls including false-negative results in early stage OvCa, and false-positives when inflammatory co-morbidities are present (2,3). Novel biomarkers for PET imaging of OvCa are avidly pursued in preclinical research including receptor overexpression, cell proliferation, vasculature, and hypoxia (3)(4)(5)(6)(7)(8)(9)(10).…”

Radioiodinated estradiol dimer for estrogen receptor targeted breast cancer imaging

“…The use of estrogen radiopharmaceuticals to image estrogen receptor (ER) in vivo has the potential to determine the ER status of breast cancer. Fluorine‐18, iodine‐131, and other radionuclides are widely used to label estrogen derivatives for in vivo imaging of ER density in steroid‐sensitive tumors (Ali, Rousseau, Gantchev, & van Lier, 1993; Ali, Rousseau, Ghaffari, & van Lier, 1988; Ali et al, 2003; Antunes et al., 2017; Gatley, Shaughnessy, & Inhorn, & Leiberman, 1981; Hochberg, 1979; Huang, Li, Lv, Liu, & Lin, 2018; Kiesewetter et al., 1984; Lim, Zheng, Berridge, & Tewson, 1996; Linden et al., 2006; Mortimer et al., 1996; Nayak et al., 2008; Neto et al., 2012; Paquette et al., 2013; Rijks et al., 1998; Symes, Coulson, & Ralphs, 1985; VanBrocklin, Carlson, Katzenellenbogen, & Welch, 1993; Xia et al., 2015; Yan et al., 2013). Among them, the most successful 18 F‐labeled estrogen derivative, 16α‐[ 18 F]fluoro‐17β‐estradiol ([ 18 F]FES), has a good affinity for ER+ tumors and predicts response to tamoxifen (Linden et al., 2006; Mortimer et al., 1996).…”

“…Just like these probes, metabolic deiodination, resulting in increased non‐specific uptake, has become a common problem with radioiodine‐labeled estrogen tracers. Therefore, few radioactive iodine‐labeled probes have reached clinical trials so far and recent studies of radioactive iodine‐125/131 labeled estrogen ligands are almost stalled while the radioactive fluorine‐18 labeled ER ligands have been developed rapidly (Antunes et al., 2017; Huang et al., 2018).…”