胱氨酸转运蛋白,系统xC-,在维持氧化还原稳态中起着至关重要的作用,据报道在几种癌症亚型中过度表达。5-[18F]氟氨基辛二酸([18F]FASu)是一种新型的正电子发射断层扫描(PET)示踪剂,通过系统xC-表现出特异性摄取。[18F]通过常用的Kryptofix2.2.2/K2CO3促进氟化方法合成FASu得到四种非对映异构体,作为示踪剂位置2和5的2手性中心的结果。我们最近报道了从手性前体合成光学纯的2S-[18F]FASu。我们的初步结果表明,与2R-[18F]FASu相比,肿瘤细胞优先吸收2S异构体。很少有研究研究了手性18F标记的氨基酸的生物分布。本研究的目的是评估5位非对映体以及外消旋(2S,5R/S-)在三种不同的肿瘤模型中的混合物。
在乳腺癌(MDA-MB-231)中进行了体外示踪剂摄取实验和蛋白质印迹,胶质母细胞瘤(U-87),和前列腺癌(PC-3)细胞系。在携带异种移植物的免疫受损的Rag2M雌性小鼠中进行PET成像和生物分布研究。
所有三种示踪剂构象均允许在注射后1小时(对于U-87和PC-3肿瘤)或2小时(对于MDA-MB-231异种移植物)观察肿瘤异种移植物,与外消旋体(2S,5R/S-)与5位非对映异构体和2S相比,显示相似的图像对比度,5S-[18F]FASu构象对于成像U-87和PC-3异种移植物表现出相对较高的对比度。过量的非放射性标准阻止了异构体的肿瘤摄取,氨基辛二酸(ASu),确认目标特异性。所有三种异构体均通过肾脏途径排泄。生物分布分析表明,PC-3肿瘤具有最高的示踪剂摄取,和2S的累积(%ID/g),5R/S-,2S,5S-,和2S,5R-异构体在注射后1小时分别为9.19±1.14、8.00±1.41和7.16±2.13,分别。这给出了相应的肿瘤肌肉比分别为33.68±9.52、31.42±4.54和25.33±4.97。
我们的数据表明,纯2S-[18F]FASu可用于各种癌症的非侵入性成像系统xC-,作为外消旋混合物(2S,5R/S-)或光学纯形式。此外,这项工作显示了[18F]FASu用于检测胶质母细胞瘤和前列腺癌的潜在用途。
The cystine transporter, system xC-, plays a crucial role in sustaining redox homeostasis and is reported to be overexpressed in several cancer subtypes. 5-[18F]Fluoroaminosuberic acid ([18F]FASu) is a novel positron emission tomography (PET) tracer, which exhibits specific uptake via system xC-. [18F]FASu synthesis by the commonly used Kryptofix 2.2.2/K2CO3-facilitated fluorination method results in four diastereomers, as a result of 2 chiral centers at positions 2- and 5- of the tracer. We recently reported the synthesis of the optically pure 2S-[18F]FASu from chiral precursors. Our preliminary results indicated preferential uptake of the 2S-isomer by tumor cells compared to 2R-[18F]FASu. Few studies have investigated the biodistribution of chiral 18F-labeled amino acids. The aim of this study was to evaluate the imaging utility and biodistribution of the 5-position diastereomers as well as the racemic (2S,5R/S-) mixture in three different tumor models.
In vitro tracer uptake experiments and Western blotting were performed in breast cancer (MDA-MB-231), glioblastoma (U-87), and prostate (PC-3) cancer cell lines. PET imaging and biodistribution studies were conducted in xenograft-bearing immunocompromised Rag2M female mice.
All three tracer conformations allowed for the visualization of tumor xenografts at 1 h (for U-87 and PC-3 tumors) or 2 h (in the case of MDA-MB-231 xenografts) post-injection, with the racemate (2S,5R/S-) displaying similar image contrast as compared to the 5- position diastereomers and the 2S,5S-[18F]FASu conformation exhibiting relatively higher contrast for imaging U-87 and PC-3 xenografts. Tumor uptake of the isomers was blocked by an excess of the non-radioactive standard, aminosuberic acid (ASu), confirming target specificity. All three isomers were excreted via the renal pathway. Biodistribution analyses showed that PC-3 tumors had the highest tracer uptake, and the accumulation (%ID/g) of the 2S,5R/S-, 2S,5S-, and 2S,5R- isomers was 9.19 ± 1.14, 8.00 ± 1.41, and 7.16 ± 2.13 at 1 h post-injection, respectively. This gave corresponding tumor-to-muscle ratios of 33.68 ± 9.52, 31.42 ± 4.54, and 25.33 ± 4.97, respectively.
Our data suggest that pure 2S-[18F]FASu can be used to noninvasively image system xC- in a variety of cancers, either as the racemic mixture (2S,5R/S-) or optically pure form. Furthermore, this work shows potential utility of [18F]FASu for detection of glioblastoma and prostate cancer.