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线性和支链排列的靶向碳酸酐酶-IX的三功能放射性配体的比较。

Comparison of carbonic anhydrase-IX-targeted trifunctional radioligands between linear- and branched-chain arrangements.

作者信息

Nakashima Kazuma, Ichinose Takayoshi, Watanabe Hiroyuki, Ono Masahiro

机构信息

Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.

出版信息

Front Nucl Med. 2025 Apr 16;5:1585027. doi: 10.3389/fnume.2025.1585027. eCollection 2025.

DOI:10.3389/fnume.2025.1585027
PMID:40308720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12040898/
Abstract

BACKGROUND

Carbonic anhydrase-IX (CA-IX) is overexpressed in tumors due to hypoxic conditions and considered an attractive biomarker for tumor-targeting radioligands. The introduction of an albumin binder (ALB) to radioligands can delay their renal clearance, resulting in increased radioactivity delivered to tumors and decreased renal uptake of radioligands. In this study, we designed novel CA-IX-targeted trifunctional radioligands consisting of imidazothiadiazole sulfonamide (IS) as a CA-IX-targeted ligand, DOTA as a chelator with four free carboxylic groups, and lysine-conjugated 4-(-iodophenyl)butyric acid (Lys-IPBA) as ALB, with IS-[In]In-DOTADG-ALB in a linear-chain arrangement and [In]In-DOTAGA-ALB-IS in a branched-chain arrangement. Fundamental properties of IS-[In]In-DOTADG-ALB and [In]In-DOTAGA-ALB-IS were evaluated by and assays.

METHODS

IS-DOTADG-ALB and DOTAGA-ALB-IS were synthesized and radiolabeled with [In]InCl. The stability of IS-[In]In-DOTADG-ALB and [In]In-DOTAGA-ALB-IS was evaluated by HPLC analysis after incubation in murine plasma. A cell saturation binding assay using CA-IX-positive HT-29 cells and albumin-binding assay were performed for IS-[In]In-DOTADG-ALB and [In]In-DOTAGA-ALB-IS to evaluate their capacity to bind CA-IX and albumin. Biodistribution assays of IS-[In]In-DOTADG-ALB and [In]In-DOTAGA-ALB-IS were performed using HT-29 tumor-bearing mice to evaluate their pharmacokinetics.

RESULTS

IS-[In]In-DOTADG-ALB and [In]In-DOTAGA-ALB-IS were successfully synthesized by ligand substitution reaction from their corresponding precursors. IS-[In]In-DOTADG-ALB and [In]In-DOTAGA-ALB-IS exhibited similar stabilities in murine plasma and affinities to CA-IX, although the affinities to albumin were higher for [In]In-DOTAGA-ALB-IS compared with IS-[In]In-DOTADG-ALB. In the biodistribution assays, [In]In-DOTAGA-ALB-IS showed higher blood retention and tumor accumulation and lower renal uptake than IS-[In]In-DOTADG-ALB, reflecting their albumin-binding affinities.

CONCLUSION

These data suggest that the branched-chain arrangement of DOTAGA-ALB-IS may be useful for the design of CA-IX-targeted radioligands consisting of an IS ligand, DOTA, and Lys-IPBA.

摘要

背景

碳酸酐酶IX（CA-IX）在肿瘤中因缺氧条件而过度表达，被认为是肿瘤靶向放射性配体的一个有吸引力的生物标志物。在放射性配体中引入白蛋白结合剂（ALB）可延迟其肾脏清除，导致递送至肿瘤的放射性增加，且放射性配体的肾脏摄取减少。在本研究中，我们设计了新型的靶向CA-IX的三功能放射性配体，其由作为靶向CA-IX配体的咪唑并噻二唑磺酰胺（IS）、作为具有四个游离羧基的螯合剂的DOTA以及赖氨酸缀合的4-（-碘苯基）丁酸（Lys-IPBA）作为ALB组成，其中IS-[铟]铟-DOTADG-ALB呈线性链排列，[铟]铟-DOTAGA-ALB-IS呈支链排列。通过[具体实验名称1]和[具体实验名称2]测定评估了IS-[铟]铟-DOTADG-ALB和[铟]铟-DOTAGA-ALB-IS的基本性质。

方法

合成了IS-DOTADG-ALB和DOTAGA-ALB-IS并用[铟]铟氯化物进行放射性标记。在小鼠血浆中孵育后，通过高效液相色谱分析评估IS-[铟]铟-DOTADG-ALB和[铟]铟-DOTAGA-ALB-IS的稳定性。使用CA-IX阳性的HT-29细胞进行细胞饱和结合测定以及白蛋白结合测定，以评估IS-[铟]铟-DOTADG-ALB和[铟]铟-DOTAGA-ALB-IS结合CA-IX和白蛋白的能力。使用荷HT-29肿瘤小鼠进行IS-[铟]铟-DOTADG-ALB和[铟]铟-DOTAGA-ALB-IS的生物分布测定，以评估其药代动力学。

结果

通过相应前体的配体取代反应成功合成了IS-[铟]铟-DOTADG-ALB和[铟]铟-DOTAGA-ALB-IS。IS-[铟]铟-DOTADG-ALB和[铟]铟-DOTAGA-ALB-IS在小鼠血浆中表现出相似的稳定性以及对CA-IX的亲和力，尽管[铟]铟-DOTAGA-ALB-IS与IS-[铟]铟-DOTADG-ALB相比对白蛋白的亲和力更高。在生物分布测定中，[铟]铟-DOTAGA-ALB-IS显示出比IS-[铟]铟-DOTADG-ALB更高的血液滞留和肿瘤蓄积以及更低的肾脏摄取，这反映了它们对白蛋白的结合亲和力。

结论

这些数据表明，DOTAGA-ALB-IS的支链排列可能有助于设计由IS配体、DOTA和Lys-IPBA组成的靶向CA-IX的放射性配体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/aa5c25a35dd4/fnume-05-1585027-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/b6d36ed3a1b0/fnume-05-1585027-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/fc31e2026a63/fnume-05-1585027-i001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/13322f263961/fnume-05-1585027-i002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/2539ea74fdc9/fnume-05-1585027-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/01bd4a7eff56/fnume-05-1585027-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/37b2a087251c/fnume-05-1585027-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/2067bf0e38bb/fnume-05-1585027-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/6ea2abdae81f/fnume-05-1585027-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/aa5c25a35dd4/fnume-05-1585027-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/b6d36ed3a1b0/fnume-05-1585027-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/fc31e2026a63/fnume-05-1585027-i001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/13322f263961/fnume-05-1585027-i002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/2539ea74fdc9/fnume-05-1585027-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/01bd4a7eff56/fnume-05-1585027-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/37b2a087251c/fnume-05-1585027-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/2067bf0e38bb/fnume-05-1585027-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/6ea2abdae81f/fnume-05-1585027-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d788/12040898/aa5c25a35dd4/fnume-05-1585027-g007.jpg

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