Albumin-Binding Moieties Tune the Pharmacokinetics and Tumor Uptake of 177Lu-Labeled GRPR Radioligands

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-04 DOI:10.1021/acsmedchemlett.6c00338

Karim Obeid, Esther Olaniran Håkansson, Ekaterina Bezverkhniaia, Bobo Skillinghaug, Ulrika Rosenström, Panagiotis Kanellopoulos, Anna Orlova, Luke R. Odell

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引用次数: 0

Abstract

Although the gastrin-releasing peptide receptor (GRPR) is an established theranostic target across multiple cancers, many GRPR-targeting peptides undergo rapid renal clearance, limiting tumor uptake and therapeutic exposure. Albumin-binding moieties (ABMs) reversibly interact with serum albumin, prolonging systemic exposure and increasing the opportunity for tumor uptake. To examine how ABM structure and placement affect this behavior, we prepared four DOTA-functionalized GRPR-targeting conjugates, varying both ABM lipophilicity and position relative to the DOTA chelator. The conjugates were radiolabeled with lutetium-177 in radiochemical yields and purities of >98%. All radioconjugates retained GRPR-mediated uptake in PC-3 cells, exhibited subnanomolar receptor affinity and enhanced blood retention. [¹⁷⁷Lu]Lu-CA6356, bearing a 4-(p-iodophenyl)butyric acid-derived ABM, achieved the highest tumor uptake in PC-3 xenografts at 4 h pi (12 ± 2% IA/g), which increased by approximately 30% 24 h pi. These findings show that ABM identity and placement can modulate systemic exposure and tumor uptake in GRPR-targeting radioligands.

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白蛋白结合部分调节177lu标记的GRPR放射配体的药代动力学和肿瘤摄取

虽然胃泌素释放肽受体（GRPR）是多种癌症的既定治疗靶点，但许多GRPR靶向肽经历快速的肾脏清除，限制了肿瘤的摄取和治疗暴露。白蛋白结合部分（ABMs）可逆地与血清白蛋白相互作用，延长全身暴露并增加肿瘤摄取的机会。为了研究ABM的结构和位置如何影响这种行为，我们制备了四个DOTA功能化的grpr靶向偶联物，改变了ABM的亲脂性和相对于DOTA螯合剂的位置。这些偶联物用镥-177进行放射性标记，放射化学产率和纯度为98%。所有放射性缀合物在PC-3细胞中保留grpr介导的摄取，表现出亚纳米摩尔受体的亲和力和增强的血液潴留。[177Lu]Lu-CA6356携带4-（对碘苯基）丁酸衍生的ABM，在4 h（12±2% IA/g）时，在PC-3异种移植物中获得最高的肿瘤摄取，24 h增加了约30%。这些发现表明，ABM的身份和位置可以调节grpr靶向放射配体的全身暴露和肿瘤摄取。

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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.