开发一种新的xCT转运体成像使用的放射性药物与抑制剂类型的化合物
IF 3
4区 医学
Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Nuclear medicine and biology
Pub Date : 2026-05-01
Epub Date: 2026-04-26
DOI:10.1016/j.nucmedbio.2026.109625
引用次数: 0
摘要
胱氨酸/谷氨酸反转运蛋白xCT因其在维持氧化还原稳态中的作用而引起了人们的关注。在肿瘤中可视化xCT表达的无创技术为评估肿瘤生物学提供了有价值的诊断信息。因此，我们开发并评估了一种新的SPECT放射性药物，以观察基于抑制剂的xCT在癌细胞中的表达。方法以xCT抑制剂磺胺嘧啶（SSZ）的结构为基础，设计合成了放射性碘化SSZ衍生物[125I]I-SSZd。我们将4-羟基- l -苯基甘氨酸（L-HPG）和4-羟基- d -苯基甘氨酸（D-HPG）放射性碘化，分别合成了[125I]I-L-HPG和[125I]I-D-HPG。在两种人源性结肠癌细胞系（LS180和DLD-1）中，采用SSZ和胱氨酸抑制试验评估了[125I]I-SSZd、[125I]I-L-HPG和[125I]I-D-HPG对xCT的亲和力。实时聚合酶链反应定量检测xCT表达。在体内，我们检测了[125I]I-L-HPG在荷瘤小鼠中的生物分布。在小鼠肝、肾匀浆中进行稳定性分析。结果[125I]I-L-HPG对xCT具有较高的亲和力。[125I]I-D-HPG对xCT有一定亲和力。xCT不参与[125I]I-SSZd积累。xCT基因在LS180细胞中的表达水平高于DLD-1细胞。[125I]I-L-HPG和[125I]I-D-HPG在LS180细胞中有较高的积累。[125I]I-L-HPG在两种细胞系中的积累量均高于[125I]I-D-HPG。在肾脏中，[125I]I-L-HPG的积累随着时间的推移而减少。在甲状腺中，[125I]I-L-HPG的积累随着时间的推移而增加；然而，在小鼠中没有发生脱碘。两种类型荷瘤小鼠几乎在所有时间点的肿瘤与肌肉之比均为2.0，在xCT高表达的LS180肿瘤中，肿瘤与大肠之比最高达到4.0。结论在肿瘤中，[125I]I-L-HPG对xCT具有高亲和力，有望成为放射性药物。本文章由计算机程序翻译，如有差异，请以英文原文为准。
Development of a novel xCT transporter imaging using a radiopharmaceutical with inhibitor-type compounds
Background
The cystine/glutamate antiporter xCT has attracted attention due to its role in maintaining redox homeostasis. Noninvasive techniques for visualizing xCT expression in tumors provide valuable diagnostic information for evaluating tumor biology. Therefore, we developed and evaluated a novel SPECT radiopharmaceutical to visualize xCT expression in cancer cells based on inhibitors.
Methods
We designed and synthesized a radioiodinated SSZ derivative ([125I]I-SSZd), based on the structure of sulfasalazine (SSZ)—an xCT inhibitor. We radioiodinated 4-hydroxy-L-phenylglycine (L-HPG) and 4-hydroxy-D-phenylglycine (D-HPG) to synthesize [125I]I-L-HPG and [125I]I-D-HPG, respectively. The affinities of [125I]I-SSZd, [125I]I-L-HPG, and [125I]I-D-HPG to xCT were evaluated using SSZ and cystine inhibition assays in two human-derived colon cancer cell lines (LS180 and DLD-1). xCT expression was quantified using real-time polymerase chain reaction. In vivo, the biodistribution of [125I]I-L-HPG was examined in tumor-bearing mice. Stability analysis was performed in mice liver and kidney homogenates.
Results
[125I]I-L-HPG showed high affinity for xCT. [125I]I-D-HPG exhibited some affinity for xCT. xCT was not involved in [125I]I-SSZd accumulation. The gene expression levels of xCT were higher in LS180 than in DLD-1 cells. [125I]I-L-HPG and [125I]I-D-HPG showed high accumulation in LS180 cells. [125I]I-L-HPG showed higher accumulation than [125I]I-D-HPG in both cell lines. In the kidneys, [125I]I-L-HPG accumulation decreased over time. In the thyroid, [125I]I-L-HPG accumulation increased over time; however, deiodination did not occur in mice. Tumor-to-muscle ratio was >2.0 at almost all timepoints for both types of tumor-bearing mice, and the maximum tumor-to-large intestine ratio reached 4.0 in LS180 tumors with high xCT expression.
Conclusion
In tumors, [125I]I-L-HPG shows promise as a radiopharmaceutical by exhibiting high affinity for xCT.
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来源期刊
Nuclear medicine and biology
医学-核医学
CiteScore
6.00
自引率
9.70%
发文量
479
审稿时长
51 days
期刊介绍：
Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized.
These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field.
Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.
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