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-18F-fluoro-17β-estradiol (18F-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: 2-18F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol (18F-FHNP). Methods:18F-FHNP was synthesized by fluorination of the corresponding nitro precursor, followed by acidic removal of the 2-methoxyethoxymethyl protecting group. In vitro affinity of 18F-FHNP and 18F-FES for ER was evaluated in SKOV3 ovarian carcinoma cells. PET imaging and ex vivo biodistribution studies with 18F-FHNP and 18F-FES were conducted in athymic nude mice bearing a SKOV3 xenografts. Results:18F-FHNP had nanomolar affinity for ERs, with a 3.5 times higher affinity for ERβ. 18F-FHNP was obtained in 15%-40% radiochemical yield (decay-corrected), with a specific activity of 279 ± 75 GBq/μmol. 18F-FHNP had a dissociation constant of 2 nM and maximum binding capacity of 18 fmol/106 cells, and 18F-FES had a dissociation constant of 3 nM and maximum binding capacity 83 fmol/106 SKOV3 cells. Both 18F-FHNP and 18F-FES PET could clearly visualize the tumor in male mice bearing a SKOV3 xenograft. Biodistribution studies showed similar distribution of 18F-FHNP and 18F-FES in most peripheral organs. 18F-FES showed a 2-fold-higher tumor uptake than 18F-FHNP. The tumor-to-plasma ratio of 18F-FES decreased 55% (P = 0.024) and 8% (P = 0.68) when administered in the presence of estradiol (nonselective) and genistein (ERβ-selective), respectively. The tumor-to-plasma ratio of 18F-FHNP decreased 41% (P = 0.004) and 64% (P = 0.0009) when administered with estradiol and genistein, respectively. Conclusion: The new PET tracer 18F-FHNP has suitable properties for imaging and shows relative selectivity for ERβ.