Transthyretin binders have previously been used to improve the pharmacokinetic properties of small-molecule drug conjugates and could, thus, be utilized for radiopharmaceuticals as an alternative to the widely explored “albumin binder concept”. In this study, a novel PSMA ligand modified with a transthyretin-binding entity (TB-01) was synthesized and labeled with lutetium-177 to obtain [177Lu]Lu-PSMA-TB-01. A high and specific uptake of [177Lu]Lu-PSMA-TB-01 was found in PSMA-positive PC-3 PIP cells (69 ± 3% after 4 h incubation), while uptake in PSMA-negative PC-3 flu cells was negligible (<1%). In vitro binding studies showed a 174-fold stronger affinity of [177Lu]Lu-PSMA-TB-01 to transthyretin than to human serum albumin. Biodistribution studies in PC-3 PIP/flu tumor-bearing mice confirmed the enhanced blood retention of [177Lu]Lu-PSMA-TB-01 (16 ± 1% IA/g at 1 h p.i.), which translated to a high tumor uptake (69 ± 13% IA/g at 4 h p.i.) with only slow wash-out over time (31 ± 8% IA/g at 96 h p.i.), while accumulation in the PC-3 flu tumor and non-targeted normal tissue was reasonably low. Further optimization of the radioligand design would be necessary to fine-tune the biodistribution and enable its use for therapeutic purposes. This study was the first of this kind and could motivate the use of the “transthyretin binder concept” for the development of future radiopharmaceuticals.
转甲状腺素蛋白结合剂先前已被用于改善小分子药物偶联物的药代动力学特性，因此可作为广泛研究的“白蛋白结合剂概念”的替代方案，应用于放射性药物开发。本研究合成了一种经转甲状腺素蛋白结合结构修饰的新型PSMA配体（TB-01），并用镥-177标记获得[¹⁷⁷Lu]Lu-PSMA-TB-01。在PSMA阳性的PC-3 PIP细胞中观察到[¹⁷⁷Lu]Lu-PSMA-TB-01具有高特异性摄取（孵育4小时后达69±3%），而在PSMA阴性的PC-3 flu细胞中摄取可忽略不计（<1%）。体外结合实验显示，[¹⁷⁷Lu]Lu-PSMA-TB-01与转甲状腺素蛋白的亲和力是与人血清白蛋白的174倍。在PC-3 PIP/flu荷瘤小鼠中的生物分布研究证实，[¹⁷⁷Lu]Lu-PSMA-TB-01具有增强的血浆滞留性（注射后1小时达16±1% IA/g），并转化为高肿瘤摄取（注射后4小时达69±13% IA/g），且随时间推移仅缓慢洗脱（注射后96小时为31±8% IA/g），而在PC-3 flu肿瘤和非靶向正常组织中的蓄积保持在合理较低水平。未来需通过进一步优化放射性配体设计来精细调控其生物分布，以实现治疗应用。本研究是该领域的首次探索，有望推动“转甲状腺素蛋白结合剂概念”在未来放射性药物开发中的应用。
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