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About 75% of breast tumors show an overexpression of the estradiol receptor (ER), making it a valuable target for tumor diagnosis and therapy. To date, 16α-[¹⁸F]fluoroestradiol (FES) is the only FDA-approved imaging probe for the positron emission tomography (PET) imaging of ER-positive (ER⁺⁾ breast cancer. However, FES has the drawback of a high retention in the liver. Therefore, the aim of this study was the development and preclinical evaluation of estradiol (E2) derivatives with different lipophilicity. Three ¹⁸F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by ¹⁸F-CuAAC (Cu-catalyzed azide-alkyne cycloaddition). The cellular uptake in ER⁺ MCF-7 tumor cells was highest for the less hydrophilic derivative (¹⁸F-TA-Glyco-EE). In nude mice bearing different breast tumors (ER⁺ MCF-7 and T47D versus ER⁻ MDA-MB-231), ¹⁸F-TA-Glyco-EE revealed a high uptake in the liver (13%ID/g, 30 min p.i.), which decreased over 90 min to 1.2%ID/g, indicating fast hepatobiliary clearance. The statistically significant difference of ¹⁸F-TA-Glyco-EE uptake in T47D compared to MDA-MB-231 tumors at 60–90 min p.i. indicated ER-specific uptake, whereas in vivo PET imaging did not provide evidence for specific uptake of ¹⁸F-TA-Glyco-EE in MCF-7 tumors, probably due to ER occupation by E2 after E2-dependent MCF-7 tumor growth in mice. However, in vitro autoradiography revealed a high specific binding of ¹⁸F-TA-Glyco-EE to ER⁺ tumor slices. We conclude that ¹⁸F-TA-Glyco-EE, with its increased hydrophilicity after deacetylation in the blood and thus rapid washout from non-target tissues, may be a viable alternative to FES for the PET imaging of breast cancer. Full article

In the field of ¹⁸F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective ¹⁸F-labeling of biomolecules. Among those, chemoselective ¹⁸F-fluoroglycosylation methods focus on the sweetening of pharmaceutical radiochemistry by offering a highly valuable tool for the synthesis of ¹⁸F-glycoconjugates with suitable in vivo properties for PET imaging studies. A previous review covered the various ¹⁸F-fluoroglycosylation methods that were developed and applied as of 2014 (Maschauer and Prante, BioMed. Res. Int. 2014, 214748). This paper is an updated review, providing the recent progress in ¹⁸F-fluoroglycosylation reactions and the preclinical application of ¹⁸F-glycoconjugates, including small molecules, peptides, and high-molecular-weight proteins. Full article