B2R-Targeting Radiotracer for PET/MR Imaging of Hepatocellular Carcinoma and Guiding Anti-B2R Therapy

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-06-13 DOI:10.1021/acsmedchemlett.4c00155

Ke Cai, Yunzhu Zhu, Yifan Zheng, Hui Wang and Yinfeng Qian*,

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Abstract

The bradykinin B2 receptor (B2R) is overexpressed in a wide variety of tumors and is a well-defined target for tumor imaging and therapy. The hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) scanner is considered a noninvasive and advanced instrument for precise tumor imaging. In this work, we developed a novel B2R-targeting radiotracer, ⁶⁸Ga-DOTA-icatibant, for quantifying B2R expression. ⁶⁸Ga-DOTA-icatibant showed high stability, fast clearance and specific binding to B2R. PET/MR imaging revealed excellent tumor accumulation, and the uptake in tumors could be blocked by DOTA-icatibant. Icatibant-mediated anti-B2R therapy downregulated B2R expression in tumor cells and inhibited the growth of HepG2 tumors, and the decrease in tumor uptake was monitored by timely PET/MR imaging. Hematoxylin and eosin (H&E) and immunohistochemical staining results further demonstrated that the efficacy of anti-B2R could be accurately monitored with the developed PET/MR imaging radiotracer. ⁶⁸Ga-DOTA-icatibant can be utilized to noninvasively determine B2R expression and dynamically and sensitively monitor the efficacy of anti-B2R therapy.

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用于肝细胞癌 PET/MR 成像和指导抗 B2R 治疗的 B2R 靶向放射性示踪剂

缓激肽 B2 受体（B2R）在多种肿瘤中过度表达，是肿瘤成像和治疗的明确靶点。正电子发射计算机断层扫描/磁共振成像（PET/MRI）混合扫描仪被认为是精确肿瘤成像的无创先进仪器。在这项工作中，我们开发了一种新型的 B2R 靶向放射性示踪剂 68Ga-DOTA-icatibant，用于量化 B2R 的表达。68Ga-DOTA-icatibant具有高稳定性、快速清除和与B2R特异性结合的特点。PET/MR 成像显示了良好的肿瘤蓄积性，而且 DOTA-icatibant 可以阻断肿瘤的摄取。伊卡替班介导的抗B2R治疗可降低肿瘤细胞中B2R的表达，抑制HepG2肿瘤的生长，并通过及时的PET/MR成像监测肿瘤摄取量的减少。血红素和伊红（H&E）及免疫组化染色结果进一步证明，抗B2R的疗效可通过所开发的PET/MR成像放射性示踪剂得到准确监测。68Ga-DOTA-icatibant可用于无创测定B2R的表达，并动态、灵敏地监测抗B2R治疗的疗效。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.