Novel 7α-alkoxy-17α-(4′-halophenylethynyl)estradiols as potential SPECT/PET imaging agents for estrogen receptor expressing tumours: Synthesis and binding affinity evaluation

Neto, Carina; Oliveira, Maria Cristina; Gano, Lurdes; Marques, Fernanda; Yasuda, Takumi; Thiemann, Thies; Knieß, Torsten; Santos, Isabel

doi:10.1016/j.steroids.2012.05.004

Cited by 13 publications

(54 citation statements)

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“…One key advantage of technetium comes from its rich chemical behavior that can assume a large spectrum of structural arrangements, the most important being the [Tc(CO) 3 ] + (carbonyl), [TcN] 2+ (nitrido), and [ReTcO] 3+ (oxo) cores (Arterburn, Corona, Rao, Carlson, & Katzenellenbogen, ; Mull, Sattigeri, Rodriguez, & Katzenellenbogen, ; Neto et al, ; Takahashi et al, ; Wüst, Spies, & Johannsen, ; Xia et al, ). The selection of the adequate combination of metal core and chelator is essential to allow a fine‐tuning of the physicochemical and biological properties of the resulting radiopharmaceutical (Bandoli, Dolmella, Porchia, Refosco, & Tisato, ; Bolzati et al, ; Pasqualini & Duatti, ).…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of a ^99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

et al. 2019

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The aim of this work was to develop and evaluate a 99m Tc-labeled neuropeptide Y derivative with affinity toward Y1-receptor. The selected amino acid sequence included nine amino acids derived from the C-terminal portion of the NPY complemented with the addition of one cysteine-mercaptoacetic acid moiety to bind the radiometal. Labeling was achieved through the preparation of a 3 + 1 nitrido complex. Physicochemical evaluation, cell uptake, internalization and externalization studies, and competitive assays were performed. Biodistribution experiments were carried out in normal and tumor-bearing mice. A single product with radiochemical purity >90% and high stability was obtained. In vitro analysis showed specific cellular uptake, IC 50 of 73.2 nM, and a high internalization rate (80%). Biodistribution studies showed low blood and renal uptake and combined hepatobiliary and urinary elimination. Preliminary studies in mice bearing induced breast tumors rendered promising uptake values. K E Y W O R D Sbreast cancer, neuropeptide Y, radiolabeling, scintigraphy, technetium

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Section: Introductionmentioning

confidence: 99%

Development and characterization of a ^99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

et al. 2019

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“…Currently, 16b- 18 F-fluoro-16a-estradiol ( 18 F-FES) is used as a PET tracer for the clinical assessment of the ER status in patients with a clinical dilemma (7,8). In a high percentage of the patients, 18 F-FES PET actually caused a change in treatment regimen, indicating that ER imaging can indeed have an important impact on patient management (8). However, 18 F-FES possesses a weak subtype selectivity (ERa/ERb 5 2.5) (9).…”

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confidence: 99%

“…In a high percentage of the patients, 18 F-FES PET actually caused a change in treatment regimen, indicating that ER imaging can indeed have an important impact on patient management (8). However, 18 F-FES possesses a weak subtype selectivity (ERa/ERb 5 2.5) (9). Therefore, 18 F-FES PET can provide accurate information about ER expression, but not about the ER phenotype.…”

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confidence: 99%

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

et al. 2016

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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.

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“…Physicochemical properties are adequate for biological membrane penetration. In vitro studies in cells bearing estrogen receptors showed promising results, particularly a cell uptake in the same range of other 99m Tc‐labelled estradiol derivatives from the literature . However, the efflux studies demonstrated that more than 50% of the activity is quickly released from the cell.…”

Section: Discussionmentioning

confidence: 93%

“…In vitro studies in cells bearing estrogen receptors showed promising results, particularly a cell uptake in the same range of other 99m Tc-labelled estradiol derivatives from the literature. [16][17][18] However, the efflux studies demonstrated that more than 50% of the activity is quickly released from the cell. Furthermore, the in vivo studies showed that in spite of the good physicochemical properties the activity in liver and gastrointestinal tract is high, which is suboptimal for diagnosis or therapy.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Tejería

Giglio

Dematteis

et al. 2017

Labelled Comp Radiopharmac

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Assessment of the presence of estrogen receptors in breast cancer is crucial for treatment planning. With the objective to develop a potential agent for estrogen receptors imaging, we present the development and characterization of a Tc-tricarbonyl-labelled estradiol derivative. Using ethinylestradiol as starting material, an estradiol derivative bearing a 1,4-disubstituted 1,2,3-triazole-containing tridentate ligand system was synthesized by "Click Chemistry" and fully characterized. Labelling with high yield and radiochemical purity was achieved through the formation of a Tc-tricarbonyl complex. The radiolabelled compound was stable, exhibited moderate binding to plasma protein (approximately 33%) and lipophilicity in the adequate range (logP 1.3 ± 0.1 at pH 7.4). Studies in MCF7 showed promising uptake values (approximately 2%). However, more than 50% of the activity is quickly released from the cell. Biodistribution experiments in normal rats confirmed the expected "in vivo" stability of the radiotracer but showed very high gastrointestinal and liver activity, which is inconvenient for in vivo applications. Taking into consideration the well-documented influence of the chelating system in the physicochemical and biological behaviour of technetium-labelled small biomolecules, research will be continued using the same pharmacophore but different complexation modalities of technetium.

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Novel 7α-alkoxy-17α-(4′-halophenylethynyl)estradiols as potential SPECT/PET imaging agents for estrogen receptor expressing tumours: Synthesis and binding affinity evaluation

Cited by 13 publications

References 50 publications

Development and characterization of a ^99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

Development and characterization of a ^99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

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

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

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Novel 7α-alkoxy-17α-(4′-halophenylethynyl)estradiols as potential SPECT/PET imaging agents for estrogen receptor expressing tumours: Synthesis and binding affinity evaluation

Cited by 13 publications

References 50 publications

Development and characterization of a 99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

Development and characterization of a 99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

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

Development and characterization of a 99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging

Contact Info

Product

Resources

About

Development and characterization of a ^99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

Development and characterization of a ^99mTc‐labeled Neuropeptide Y short analog with potential application in breast cancer imaging

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

Development and characterization of a ^99mTc‐tricarbonyl–labelled estradiol derivative obtained by “Click Chemistry” with potential application in estrogen receptors imaging