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. Three18F-labeled prosthetic groups (two glycosyl and one PEG azide) were chosen for conjugation with ethinyl estradiol (EE) by18F-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 of18F-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 of18F-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 of18F-TA-Glyco-EE to ER+tumor slices. We conclude that18F-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.
约75%的乳腺肿瘤呈现雌二醇受体（ER）过表达，这使其成为肿瘤诊断与治疗的重要靶点。迄今为止，16α-[18F]氟代雌二醇（FES）是美国食品药品监督管理局（FDA）唯一批准用于ER阳性（ER+）乳腺癌正电子发射断层扫描（PET）成像的显像探针。然而，FES存在肝脏滞留率高的缺点。因此，本研究旨在开发并临床前评估具有不同亲脂性的雌二醇（E2）衍生物。研究选取三种18F标记的辅助基团（两种糖基化及一种聚乙二醇叠氮化物），通过18F-铜催化叠氮-炔环加成反应（CuAAC）与炔雌醇（EE）进行偶联。在ER阳性MCF-7肿瘤细胞中，亲水性较低的衍生物（18F-TA-Glyco-EE）表现出最高的细胞摄取率。在携带不同乳腺肿瘤（ER阳性MCF-7和T47D vs ER阴性MDA-MB-231）的裸鼠实验中，18F-TA-Glyco-EE在肝脏呈现高摄取（注射后30分钟达13%ID/g），90分钟内降至1.2%ID/g，表明其具有快速的肝胆清除特性。注射后60-90分钟，T47D肿瘤与MDA-MB-231肿瘤对18F-TA-Glyco-EE的摄取存在统计学显著差异，提示ER特异性摄取；而体内PET成像未显示18F-TA-Glyco-EE在MCF-7肿瘤中的特异性摄取，这可能源于小鼠体内E2依赖性MCF-7肿瘤生长导致的ER被E2占据。然而，体外放射自显影证实18F-TA-Glyco-EE与ER阳性肿瘤切片具有高特异性结合。我们得出结论：18F-TA-Glyco-EE在血液中脱乙酰化后亲水性增强，从而能快速从非靶组织清除，可能成为乳腺癌PET成像中替代FES的可行方案。
肿瘤(癌症)患者之家