Functional imaging of oxidative stress with a novel PET imaging agent, 18F-5-fluoro-L-aminosuberic acid.
Functional imaging of oxidative stress with a novel PET imaging agent, 18F-5-fluoro-L-aminosuberic acid.
复制标题
DOI：
10.2967/jnumed.113.126664
复制
发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Schaffer P
中科院分区：
文献类型：
--
作者：
Webster JM;Morton CA;Johnson BF;Yang H;Rishel MJ;Lee BD;Miao Q;Pabba C;Yapp DT;Schaffer P
谷胱甘肽是细胞内主要的内源性抗氧化剂，通过中和自由基和活性氧物种，在细胞对氧化应激的防御反应中发挥关键作用。由于半胱氨酸是谷胱甘肽生物合成的限速底物，半胱氨酸/谷氨酸转运体(系统XC−)是一种潜在的有吸引力的正电子发射计算机断层扫描生物标志物，可以在体内定量XC−活性，以响应与疾病相关的氧化应激。我们开发了一种系统的XC−底物，它结合了天然底物L-半胱氨酸和L-谷氨酸(L-谷氨酸)的特点。L-氨基磺酸(L-ASU)已被确定为比L-谷氨酸更有效的XCPET底物，从而评估了一系列阴离子氨基酸作为潜在的−示踪剂的前景。在此，我们报道了18F-5-氟氨基琥珀酸(18F-FASU)的合成和体内外验证，作为一种PET示踪剂，用于对具有显著肿瘤摄取和保留的细胞对氧化应激的反应进行功能成像。通过对类似于L-胱氨酸和L-谷氨酸的化合物的体外筛选，18F-FASU被确定为一种潜在的PET示踪剂。通过对氧化应激诱导的EL4和SKOV-3细胞的体外摄取和抑制研究，确定对XC−系统的亲和力。对荷瘤小鼠(EL4和SKOV-3)的体内生物分布和PET成像进行了研究。体外实验结果表明，L-ASU对XC系统−的抑制作用与L-Glu相当或更好。氚化合物摄取的直接比较表明，L-ASU比L-Glu更有效地摄取XC-−。18F-Fasu的放射合成允许在体外验证对含氟衍生物的摄取。体内评估显示，在SKOV-3肿瘤中，主要是肾脏清除和摄取每克约8%的注射剂量，肿瘤与血液和肿瘤与肌肉的比率分别约为12和28。在SKOV-3肿瘤中，18F-Fasu摄取大约是18F-FDG摄取的5倍。动态PET成像显示EL4肿瘤移植瘤摄取了大约6%的注射剂量/克，并在注射后至少2小时内良好地保留了肿瘤。18F-Fasu是一种潜在有用的代谢示踪剂，可用于PET成像功能细胞对氧化应激的反应。在某些肿瘤中，18F-Fasu可提供比18F-FDG更敏感的检测。
Glutathione is the predominant endogenous cellular antioxidant, playing a critical role in the cellular defensive response to oxidative stress by neutralizing free radicals and reactive oxygen species. With cysteine as the rate-limiting substrate in glutathione biosynthesis, the cystine/glutamate transporter (system xc−) represents a potentially attractive PET biomarker to enable in vivo quantification of xc− activity in response to oxidative stress associated with disease. We have developed a system xc− substrate that incorporates characteristics of both natural substrates, l-cystine and l-glutamate (l-Glu). l-aminosuberic acid (l-ASu) has been identified as a more efficient system xc− substrate than l-Glu, leading to an assessment of a series of anionic amino acids as prospective PET tracers. Herein, we report the synthesis and in vitro and in vivo validation of a lead candidate, 18F-5-fluoro-aminosuberic acid (18F-FASu), as a PET tracer for functional imaging of a cellular response to oxidative stress with remarkable tumor uptake and retention. 18F-FASu was identified as a potential PET tracer based on an in vitro screening of compounds similar to l-cystine and l-Glu. Affinity toward system xc− was determined via in vitro uptake and inhibition studies using oxidative stress–induced EL4 and SKOV-3 cells. In vivo biodistribution and PET imaging studies were performed in mice bearing xenograft tumors (EL4 and SKOV-3). In vitro assay results determined that l-ASu inhibited system xc− as well as or better than l-Glu. The direct comparison of uptake of tritiated compounds demonstrated more efficient system xc− uptake of l-ASu than l-Glu. Radiosynthesis of 18F-FASu allowed the validation of uptake for the fluorine-bearing derivative in vitro. Evaluation in vivo demonstrated primarily renal clearance and uptake of approximately 8 percentage injected dose per gram in SKOV-3 tumors, with tumor-to-blood and tumor-to-muscle ratios of approximately 12 and approximately 28, respectively. 18F-FASu uptake was approximately 5 times greater than 18F-FDG uptake in SKOV-3 tumors. Dynamic PET imaging demonstrated uptake in EL4 tumor xenografts of approximately 6 percentage injected dose per gram and good tumor retention for at least 2 h after injection. 18F-FASu is a potentially useful metabolic tracer for PET imaging of a functional cellular response to oxidative stress. 18F-FASu may provide more sensitive detection than 18F-FDG in certain tumors.
登录
查看更多内容
影响因子：
2.3
作者：
Gout, PW;Simms, CR;Robertson, MC
通讯作者：
Robertson, MC
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
3
作者：
Albrecht, Philipp;Lewerenz, Jan;Methner, Axel
通讯作者：
Methner, Axel
影响因子：
8
作者：
Chen, R-S;Song, Y-M;Li, W.
通讯作者：
Li, W.
影响因子：
4.4
作者：
Domercq, Maria;Sanchez-Gomez, Maria Victoria;Matute, Carlos
通讯作者：
Matute, Carlos