title: 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 of18F-FHNP and18F-FES for ER was evaluated in SKOV3 ovarian carcinoma cells. PET imaging and ex vivo biodistribution studies with18F-FHNP and18F-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/106cells, and18F-FES had a dissociation constant of 3 nM and maximum binding capacity 83 fmol/106SKOV3 cells. Both18F-FHNP and18F-FES PET could clearly visualize the tumor in male mice bearing a SKOV3 xenograft. Biodistribution studies showed similar distribution of18F-FHNP and18F-FES in most peripheral organs.18F-FES showed a 2-fold-higher tumor uptake than18F-FHNP. The tumor-to-plasma ratio of18F-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 of18F-FHNP decreased 41% (P= 0.004) and 64% (P= 0.0009) when administered with estradiol and genistein, respectively.Conclusion:The new PET tracer18F-FHNP has suitable properties for imaging and shows relative selectivity for ERβ.
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and i.farinha.antunes@umcg.nl.
authors.forename: Inês F
authors.initials: IF
authors.lastname: Antunes
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Geke A P
authors.initials: GA
authors.lastname: Hospers
authors.affiliation: Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; and.
authors.forename: Erik F J
authors.initials: EF
authors.lastname: de Vries
mesh_terms: D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D011854:Radiochemistry; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: C000619246:2-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol; D047629:Estrogen Receptor beta; D008024:Ligands; D009281:Naphthalenes; D009284:Naphthols; D011725:Pyridines; D004958:Estradiol; C043436:16-fluoroestradiol
keywords: PET; cancer; estrogen receptors; hormones; imaging