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18F-labeled difluoroestradiols: preparation and preclinical evaluation as estrogen receptor-binding
Yann Seimbille1, Jacques Rousseau, François Bénard
1Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, Sherbrooke PET Center, Université de Sherbrooke, Sherbrooke, Que., Canada J1H 5N4.
Abstract:
A-ring fluorination of estradiol (ES) at position 2 or 4 decreases the rate of metabolism by blocking the formation of catechol estrogens, one of the major metabolic pathways of ES. We postulate that adding a 2- or 4-fluoro substituent to 16alpha-[18F]fluoroestradiol (FES), a positron emission tomography (PET) radiopharmaceutical used for estrogen receptor (ER) imaging, should prolong its blood circulation time, and thus, improve its localization in ER-rich target tissues. On such account, we prepared a series of FES derivatives substituted with a fluorine atom at C2 or C4, with or without an 11beta-OMe group, and we tested their binding affinities for the ER and different serum proteins including rat alphafetoprotein (AFP) and human sex hormone-binding globulin (SHBG). Labeling at the 16alpha-position was accomplished via nucleophilic substitution with [18F]F(-) on the reactive 16beta,17beta-cyclic sulfate intermediates. Decay corrected yields varied between 30 and 50% for a total synthesis time of 120 min, providing final products with specific activities >3000 Ci/mmol. The 18F-labeled analogs were evaluated for their biodistribution in immature female rats. Substitutions with the 4-F have little effect on binding affinities. Addition of the 2-F diminishes ER and AFP-binding affinities while augmenting the affinity for the SHBG. Addition of the 11beta-OMe decreases all binding affinities, particularly to AFP and SHBG. In contrast, biodistribution of the corresponding [16alpha-18F]fluoro analogs in immature female rats revealed that the presence of the 11beta-OMe group improves ER-mediated uterus uptake, with the 4,16alpha-[16alpha-18F]difluoro-11beta-methoxyestradiol showing the highest uptake values (15% ID at 1-h post-injection). These data suggest that the addition of both a 4-F and 11beta-OMe group onto FES may provide an improved radiopharmaceutical for PET imaging of ER densities in breast cancer patients.
Insights
Fluorine substitution on estradiol derivatives can improve their use in PET imaging. Adding a 4-fluoro and 11beta-methoxy group to 16alpha-[18F]fluoroestradiol enhances estrogen receptor imaging potential for breast cancer detection.
Area of Science:
- Radiochemistry
- Nuclear Medicine
- Medicinal Chemistry
Background:
- Estradiol (ES) metabolism involves catechol estrogen formation, a pathway blocked by A-ring fluorination.
- 16alpha-[18F]fluoroestradiol (FES) is a positron emission tomography (PET) radiopharmaceutical for estrogen receptor (ER) imaging.
- Modifying FES structure may prolong circulation time and enhance localization in ER-rich tissues.
Purpose of the Study:
- To synthesize and evaluate novel FES derivatives with fluorine at C2 or C4 and an 11beta-methoxy group.
- To assess the binding affinities of these derivatives to ER, alpha-fetoprotein (AFP), and sex hormone-binding globulin (SHBG).
- To determine the in vivo biodistribution and target tissue uptake of the novel FES analogs.
Main Methods:
- Synthesis of 16alpha-[18F]fluoroestradiol derivatives via nucleophilic substitution on cyclic sulfate intermediates.
- Radiolabeling with [18F]fluoride, achieving yields of 30-50% and specific activities >3000 Ci/mmol within 120 min.
- In vitro binding assays for ER, AFP, and SHBG, and in vivo biodistribution studies in immature female rats.
Main Results:
- 4-Fluoro substitution showed minimal impact on binding affinities.
- 2-Fluoro substitution decreased ER and AFP binding but increased SHBG affinity.
- 11beta-Methoxy substitution reduced all binding affinities, yet improved ER-mediated uterus uptake in vivo, with 4,16alpha-[16alpha-18F]difluoro-11beta-methoxyestradiol showing the highest uptake.
Conclusions:
- Structural modifications of FES can significantly alter its binding properties and biodistribution.
- The combination of 4-fluoro and 11beta-methoxy groups on FES shows promise for improved PET imaging of ER densities.
- These findings suggest potential for enhanced breast cancer imaging in clinical settings.