Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
J Med Chem. 2024 Aug 8;67(15):13491-13506. doi: 10.1021/acs.jmedchem.4c01420. Epub 2024 Jul 28.
Prostate-specific membrane antigen (PSMA) is an excellent target for cancer detection and therapy. Hypoxia is prevalent in solid tumors, and various nitroimidazole (NI) radioligands can be trapped inside hypoxic cells for diagnosis and therapy. To enhance tumor uptake and retention, we designed bivalent agents (compounds -) incorporating a hypoxia-sensitive NI-moiety and a PSMA-targeting group. Ligands - were successfully prepared and labeled with Ga or Lu. Among them, [Ga]Ga- ([Ga]Ga-AAZTA-NI-PSMA-093) demonstrated significantly higher cellular accumulation under hypoxic conditions than under normoxic conditions, suggesting hypoxia-selective trapping by the introduction of NI group. PET/CT imaging at 60 min postinjection of [Ga]Ga- revealed high tumor uptake (SUV: 10.68%ID/mL) in the tumor-bearing mice model. SPECT/CT imaging of [Lu]Lu- at 24 and 48 h postinjection demonstrated excellent accumulation and retention. Preliminary studies indicate that [Ga]Ga/[Lu]Lu- may be promising bivalent agents targeting hypoxia and PSMA binding for diagnosis and radiotherapy.
前列腺特异性膜抗原（PSMA）是癌症检测和治疗的优秀靶点。缺氧在实体瘤中很常见，各种硝基咪唑（NI）放射性配体可以被捕获在缺氧细胞内进行诊断和治疗。为了增强肿瘤摄取和保留，我们设计了双价试剂（化合物 -），其中包含一个缺氧敏感的 NI 部分和一个 PSMA 靶向基团。配体 - 成功制备并标记了 Ga 或 Lu。其中，[Ga]Ga-（[Ga]Ga-AAZTA-NI-PSMA-093）在缺氧条件下的细胞积累明显高于在常氧条件下，表明通过引入 NI 基团实现了缺氧选择性捕获。在注射 [Ga]Ga-后 60 分钟进行的 PET/CT 成像显示，荷瘤小鼠模型中的肿瘤摄取（SUV：10.68%ID/mL）非常高。在注射 [Lu]Lu-后 24 和 48 小时进行的 SPECT/CT 成像显示出优异的积累和保留。初步研究表明，[Ga]Ga/[Lu]Lu-可能是一种有前途的双价试剂，用于针对缺氧和 PSMA 结合进行诊断和放射治疗。
