Radiosynthesis and Biological Evaluation of a Small-Molecule Probe for Thyroid-Stimulating Hormone Receptor

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-07 DOI:10.1021/acsmedchemlett.5c00210

Yuanyuan Zhou, Ji Tao, Yuanpeng Jiang, Aiyan Ji, Xiangning Luo, Jin Tian, Xuanyan Zhao, Kun Qian, Chunrong Qu, Renfei Wang*, Wen-Hua Chen* and Zhen Cheng*,

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Abstract

The thyroid-stimulating hormone receptor (TSHR) plays a pivotal role in regulating thyroid growth, function, synthesis, and secretion of thyroid hormones, with its overexpression linked to various diseases, especially in tumors. A novel TSHR-targeting small molecule agonist ML-109 with a nM potency has been developed. In this study, we radiolabeled ML-109 with radionuclide iodine-131 on the quinazolin-4-one ring to prepare ¹³¹I-ML-109, and its biological performance was further evaluated as a single-photon emission computed tomography radiotracer. The results displayed that ¹³¹I-ML-109 was prepared in high radiochemical purity >95% and moderate radiolabeling yield (∼40%). Further, ¹³¹I-ML-109 demonstrated a good tumor uptake capability in both K1 and 8305C xenograft models. Overall, this study has established the synthetic strategy for preparation of ¹³¹I-ML-109, highlighting that ML-109 is a promising molecular scaffold for developing TSHR targeted imaging probe. Further structural optimization is desired to improve the diagnostic performance of the next-generation probe.

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促甲状腺激素受体小分子探针的放射合成及生物学评价

促甲状腺激素受体（TSHR）在调节甲状腺的生长、功能、甲状腺激素的合成和分泌中起着关键作用，其过表达与多种疾病，特别是肿瘤有关。研制了一种新型靶向tshr的nM效价小分子激动剂ML-109。本研究利用放射性核素碘-131在喹唑啉-4- 1环上对ML-109进行放射性标记，制备了131I-ML-109，并对其作为单光子发射计算机断层扫描放射性示踪剂的生物学性能进行了进一步评价。结果表明，制备的131I-ML-109具有较高的放射化学纯度>；95%和中等的放射性标记率（~ 40%）。此外，131I-ML-109在K1和8305C异种移植模型中均表现出良好的肿瘤摄取能力。总之，本研究建立了制备131I-ML-109的合成策略，强调ML-109是开发TSHR靶向成像探针的有前景的分子支架。需要进一步优化结构以提高下一代探针的诊断性能。

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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.