¹⁸F-labeled estradiol derivative for targeting estrogen receptor-expressing breast cancer

A novel radiotracer 1‑(2‑(2‑(2‑[¹⁸F]fluoroethoxy)ethoxy)ethyl)‑1H‑1,2,3‑triazole‑estradiol ([¹⁸F]FETE) was successfully synthesized, characterized and evaluated in mice for estrogen receptor (ER)-positive breast cancer targeting with positron emission tomography (PET) imaging.

The tosylate precursor 3 was radiolabeled with ¹⁸F and then reacted with 17α‑ethinyl‑estradiol to produce the final [¹⁸F]FETE. The physicochemical properties of [¹⁸F]FETE were tested in vitro, including determination of the octanol/water partition coefficient, stability and cellular uptake in MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) cells. An ex vivo biodistribution study was performed in normal Sprague Dawley rats, and in vivo microPET imaging was performed on MCF-7 and MDA-MB-231 tumor-bearing mice. The results of biodistribution and PET imaging of [¹⁸F]FETE were compared with that of known 16α‑[¹⁸F]fuoro‑17β‑estradiol ([¹⁸F]FES). Radiation dose estimates for [¹⁸F]FETE were also analyzed.

[¹⁸F]FETE was obtained in high radiochemical yield (46.59 ± 8.06%) with high radiochemical purity (>99%) after HPLC purification and high molar activity (15.45 ± 3.15 GBq/μmol). [¹⁸F]FETE is a moderate lipophilic compound with good in vitro stability and the total synthesis time was 55 to 65 min. In biodistribution studies, [¹⁸F]FETE showed high uptake in the ER-abundant uterine tissue of normal immature SD rats (8.55 ± 1.21 and 6.83 ± 1.70%ID/g at 1 h after intravenous and intraperitoneal injection, respectively), and could be blocked with estradiol effectively (the uterus uptake was decreased to 0.63 ± 0.35%ID/g at 1 h after iv injection). MicroPET imaging of tumor-bearing mice with [¹⁸F]FETE at 1 h after iv injection revealed considerable uptake in ER-positive MCF-7 tumors (4.63 ± 0.73%ID/g) that could be inhibited (1.47 ± 0.29%ID/g) and low uptake in ER-negative MDA-MB-231 tumors (1.97 ± 0.36%ID/g). [¹⁸F]FES has relatively low uptake in ER-positive tumor (0.24 ± 0.19%ID/g) when compared with [¹⁸F]FETE. The adult female effective radiation dose of [¹⁸F]FETE in mice was estimated as 0.0022 mSv/MBq.

A novel 17α‑ethinyl‑estradiol-based ER probe [¹⁸F]FETE was developed with high molar activity and good in vitro stability. Based on the results of bio-evaluation in normal immature rats and tumor-bearing mice, it might be a promising candidate for specific PET imaging of ER-positive breast cancer.