Development of Novel Gastrin-Releasing Peptide Receptor-Targeted Radioligand with Albumin Binder to Improve Accumulation in Tumor

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-25 DOI:10.1021/acsmedchemlett.5c0003210.1021/acsmedchemlett.5c00032

Shohei Tsuchihashi, Kazuma Nakashima, Hiroyuki Watanabe and Masahiro Ono*,

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引用次数: 0

Abstract

Gastrin-releasing peptide receptor (GRPR) is a promising target for cancer radiotheranostics combining nuclear imaging with targeted radionuclide therapy. Improving the accumulation of radioligands in tumors by introducing an albumin binder (ALB) is useful to promote the efficacy of radiotheranostics. In this study, we designed and synthesized a novel GRPR-targeted radioligand [¹¹¹In]In-AMTG-DA1 containing an ALB moiety to improve tumor accumulation. [¹¹¹In]In-AMTG-DA1 showed marked binding ability to albumin, high affinity for GRPR, and high-level stability in vitro. In biodistribution studies, the tumor accumulation of [¹¹¹In]In-AMTG-DA1 was much higher than that of the control ligand without an ALB moiety. The introduction of ALB increased the tumor area under the curve (AUC) value of [¹¹¹In]In-AMTG-DA1 by 3.5 times. In a single-photon emission computed tomography (SPECT) study, [¹¹¹In]In-AMTG-DA1 visualized a GRPR-expressing tumor clearly at 24 h postinjection. Our findings suggest the favorable pharmacokinetics of [¹¹¹In]In-AMTG-DA1 as a GRPR-targeted radioligand exhibiting a high-level accumulation in tumors.

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新型胃泌素释放肽受体靶向白蛋白结合物的研究进展

胃泌素释放肽受体（GRPR）是核显像与靶向放射性核素治疗相结合的肿瘤放射治疗的一个有前景的靶点。通过引入白蛋白结合剂（ALB）来改善肿瘤中放射配体的积累，有助于提高放射治疗的疗效。在本研究中，我们设计并合成了一种新的grpr靶向放射配体[111In]In- amtg - da1，该配体含有ALB片段，可促进肿瘤的积累。[111] in - amtg - da1具有明显的白蛋白结合能力，对GRPR具有高亲和力，体外稳定性高。在生物分布研究中，[111In]In- amtg - da1的肿瘤蓄积量远高于不含ALB片段的对照配体。ALB的引入使[111In]In-AMTG-DA1的肿瘤曲线下面积（AUC）值增加3.5倍。在单光子发射计算机断层扫描（SPECT）研究中，[111In]In- amtg - da1在注射后24小时清晰地显示了表达grpr的肿瘤。我们的研究结果表明，[111In] in - amtg - da1作为grpr靶向的放射配体在肿瘤中具有良好的药代动力学，表现出高水平的积累。

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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.