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

Introduction: A novel radiotracer 1 (2 (2 (2 [F-18]fluoroethoxy)ethoxy)ethyl) 1H 1,2,3 triazole estradiol [F-18]FETE) was successfully synthesized, characterized and evaluated in mice for estrogen receptor (ER)-positive breast cancer targeting with positron emission tomography (PET) imaging. Methods: The tosylate precursor 3 was radiolabeled with F-18 and then reacted with 17 alpha ethinyl estradiol to produce the final [F-18]FETE. The physicochemical properties of [F-18]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 16a [F-18] fuoro 17 beta estradiol ([F-18]FES). Radiation dose estimates for [F-18]FETE were also analyzed. Results: [F-18]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/pmol). [F-18]FETE is a moderate lipophilic compound with good in vitro stability and the total synthesis time was 55 to 65 min. In biodistribution studies, [F-18]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 [F-18]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 f 0.29%ID/g) and low uptake in ER-negative MDA-MB-231 tumors (1.97 +/- 0.36%ID/g). [F-18]FES has relatively low uptake in ER-positive tumor (0.24 +/- 0.19%ID/g) when compared with [F-18]FETE. The adult female effective radiation dose of [F-18]FETE in mice was estimated as 0.0022 mSv/MBq. Conclusions: A novel 17 alpha ethinyl estradiol-based ER probe [F-18]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. (C) 2018 Elsevier Inc. All rights reserved.