State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, 4221-116 Xiang'an South Rd, Xiamen 361102, China.
The First Affiliated Hospital of Xiamen University, Zhenhai Road, Xiamen 361003, China.
Nucl Med Biol. 2018 Apr;59:48-55. doi: 10.1016/j.nucmedbio.2018.01.003. Epub 2018 Feb 2.
A novel radiotracer 1‑(2‑(2‑(2‑[F]fluoroethoxy)ethoxy)ethyl)‑1H‑1,2,3‑triazole‑estradiol ([F]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 F and then reacted with 17α‑ethinyl‑estradiol to produce the final [F]FETE. The physicochemical properties of [F]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 [F]FETE were compared with that of known 16α‑[F]fuoro‑17β‑estradiol ([F]FES). Radiation dose estimates for [F]FETE were also analyzed.
[F]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). [F]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]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]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). [F]FES has relatively low uptake in ER-positive tumor (0.24 ± 0.19%ID/g) when compared with [F]FETE. The adult female effective radiation dose of [F]FETE in mice was estimated as 0.0022 mSv/MBq.
A novel 17α‑ethinyl‑estradiol-based ER probe [F]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.
一种新型放射性示踪剂 1-（2-（2-（2-[F] 乙氧基）乙氧基）乙基）-1H-1,2,3-三唑-雌二醇 ([F]FETE) 已成功合成、表征，并在小鼠中进行了正电子发射断层扫描 (PET) 成像的雌激素受体 (ER) 阳性乳腺癌靶向研究。
用 F 对 tosylate 前体 3 进行放射性标记，然后与 17α-乙炔基-雌二醇反应，得到最终的 [F]FETE。[F]FETE 的物理化学性质在体外进行了测试，包括测定辛醇/水分配系数、稳定性和 MCF-7（ER 阳性）和 MDA-MB-231（ER 阴性）细胞的摄取率。在正常 Sprague Dawley 大鼠中进行了离体生物分布研究，并在 MCF-7 和 MDA-MB-231 荷瘤小鼠中进行了体内 microPET 成像。[F]FETE 的生物分布和 PET 成像结果与已知的 16α-[F] 氟-17β-雌二醇 ([F]FES) 进行了比较。还分析了 [F]FETE 的辐射剂量估计值。
[F]FETE 经 HPLC 纯化后，放射化学产率（46.59±8.06%）高，放射化学纯度（>99%）高，摩尔放射性活度（15.45±3.15GBq/μmol）高。[F]FETE 是一种中等亲脂性化合物，具有良好的体外稳定性，总合成时间为 55-65min。在生物分布研究中，[F]FETE 在正常未成熟 SD 大鼠的 ER 丰富的子宫组织中表现出高摄取（静脉和腹腔注射后 1 小时分别为 8.55±1.21%和 6.83±1.70%ID/g），且可被雌二醇有效阻断（静脉注射后 1 小时子宫摄取率降至 0.63±0.35%ID/g）。静脉注射后 1 小时荷瘤小鼠的 microPET 成像显示，[F]FETE 在 ER 阳性 MCF-7 肿瘤中有可观的摄取（4.63±0.73%ID/g），可被抑制（1.47±0.29%ID/g），而在 ER 阴性 MDA-MB-231 肿瘤中摄取率较低（1.97±0.36%ID/g）。与 [F]FETE 相比，[F]FES 在 ER 阳性肿瘤中的摄取率相对较低（0.24±0.19%ID/g）。在小鼠中，[F]FETE 的成年雌性有效辐射剂量估计值为 0.0022mSv/MBq。
开发了一种新型基于 17α-乙炔基-雌二醇的 ER 探针 [F]FETE，具有高摩尔放射性活度和良好的体外稳定性。基于在正常未成熟大鼠和荷瘤小鼠中的生物评价结果，它可能是 ER 阳性乳腺癌特异性 PET 成像的有前途的候选物。
