Synthesis and Preclinical Evaluation of a Bispecific PSMA-617/RM2 Heterodimer Targeting Prostate Cancer

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-10-18 DOI:10.1021/acsmedchemlett.4c0032410.1021/acsmedchemlett.4c00324

Christos Liolios*, Danai Bouziotis, Wiebke Sihver, Martin Schäfer, George Lambrinidis, Evangelia-Alexandra Salvanou, Ulrike Bauder-Wüst, Martina Benesova, Klaus Kopka, Antonios Kolocouris and Penelope Bouziotis,

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Abstract

Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) have been used for diagnostic molecular imaging/therapy of prostate cancer (PCa). To address tumor heterogeneity, we synthesized and evaluated a bispecific PSMA/GRPR ligand (3) combining PSMA-617 (1) and the GRPR antagonist RM2 (2) with the radiometal chelator DOTA. 3 was radiolabeled with ⁶⁸Ga ([⁶⁸Ga]Ga-3) and ¹⁷⁷Lu ([¹⁷⁷Lu]Lu-3). [⁶⁸Ga]Ga-3 was tested in the following PCa cell lines for receptor affinity, time kinetic cell-binding/specificity, and cell-internalization: PC-3 and LNCaP. Compared to the monomers (1 and 2), ligand 3 showed specific cell binding, similar receptor affinities, and higher lipophilicity, while its internalization rates and cell-binding were superior. Docking calculations showed that 3 can have binding interactions of PSMA-617 (1) inside the PSMA receptor funnel and RM2 (2) inside the GRPR. In vivo biodistribution studies for [⁶⁸Ga]Ga-3 showed dual targeting for PSMA(+) and GRPR(+) tumors and higher tumor uptake, faster pharmacokinetic, and lower kidney uptake compared to 1 and 2

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针对前列腺癌的双特异性 PSMA-617/RM2 异构体的合成与临床前评估

前列腺特异性膜抗原（PSMA）和胃泌素释放肽受体（GRPR）已被用于前列腺癌（PCa）的分子成像诊断/治疗。为了解决肿瘤的异质性问题，我们合成并评估了一种双特异性 PSMA/GRPR 配体（3），该配体结合了 PSMA-617 (1)和 GRPR 拮抗剂 RM2 (2)以及放射性金属螯合剂 DOTA。3 被 68Ga （[68Ga]Ga-3）和 177Lu （[177Lu]Lu-3）放射性标记。在以下 PCa 细胞系中对[68Ga]Ga-3 进行了受体亲和性、时间动力学细胞结合/特异性和细胞内化测试：PC-3和LNCaP。与单体（1 和 2）相比，配体 3 显示出特异性细胞结合、相似的受体亲和力和更高的亲脂性，而其内化率和细胞结合率则更胜一筹。对接计算显示，配体 3 在 PSMA 受体漏斗内与 PSMA-617 （1）结合，在 GRPR 内与 RM2 （2）结合。[68Ga]Ga-3的体内生物分布研究显示，它对PSMA（+）和GRPR（+）肿瘤具有双重靶向性，与1和2相比，肿瘤摄取率更高、药代动力学更快、肾脏摄取率更低。

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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.

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