PDF(Pubmed)
Abstract：
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.
摘要：
大约75％的乳腺肿瘤显示雌二醇受体（ER）的过度表达，使其成为肿瘤诊断和治疗的有价值的靶点。迄今为止,16α-[18F]氟雌二醇（FES）是FDA批准的唯一用于ER阳性（ER）乳腺癌正电子发射断层扫描（PET）成像的成像探针。然而,FES具有在肝脏中高度保留的缺点。因此,这项研究的目的是开发和临床前评估具有不同亲脂性的雌二醇（E2）衍生物。选择三个18F标记的辅基(两个糖基和一个PEG叠氮化物)用于通过18F-CuAAC(Cu催化的叠氮化物-炔环加成)与乙炔基雌二醇(EE)缀合。对于亲水性较低的衍生物(18F-TA-Glyco-EE),ER+MCF-7肿瘤细胞中的细胞摄取最高。在携带不同乳腺肿瘤的裸鼠中（ER+MCF-7和T47D与ER-MDA-MB-231），18F-TA-Glyco-EE显示肝脏中的高摄取（13％ID/g，30分钟p.i.)，在90分钟内降至1.2%ID/g，表明快速的肝胆清除。在60-90分钟p.i.时，T47D中18F-TA-Glyco-EE摄取与MDA-MB-231肿瘤相比的统计学显着差异表明ER特异性摄取，而体内PET成像没有提供MCF-7肿瘤中18F-TA-Glyco-EE特异性摄取的证据，可能是由于在小鼠中E2依赖性MCF-7肿瘤生长后E2占据ER。然而,体外放射自显影显示18F-TA-Glyco-EE与ER肿瘤切片的高特异性结合。我们得出的结论是18F-TA-Glyco-EE，在血液中脱乙酰后其亲水性增加，因此从非靶组织中快速洗脱，可能是FES用于乳腺癌PET成像的可行替代方法。
