Woolley Benjamin, Wu Yue, Xiong Li, Chau Ho-Fai, Zhang Junhui, Law Ga-Lai, Wong Ka-Leung, Long Nicholas J
Department of Chemistry, Imperial College London Molecular Sciences Research Hub, 82 Wood Lane, White City Campus London W12 0BZ UK
Department of Chemistry, Hong Kong Baptist University Kowloon Tong Hong Kong SAR China.
Chem Sci. 2025 Jan 22;16(8):3588-3597. doi: 10.1039/d4sc02335h. eCollection 2025 Feb 19.
The blood-brain-barrier prevents many imaging agents and therapeutics from being delivered to the brain that could fight central nervous system diseases such as Alzheimer's disease and strokes. However, techniques such as the use of stapled peptides or peptide shuttles may allow payloads through, with bioconjugation achieved bio-orthogonal tetrazine/norbornene click chemistry. A series of lanthanide-tetrazine probes have been synthesised herein which could be utilised in bio-orthogonal click chemistry with peptide-based delivery systems to deliver MRI agents through the blood-brain-barrier. The Gd complexes show higher relaxivities than the clinical standard of Gd(DOTA) at 1.4 T and phosphorescence is observed from the Eu and Tb complexes tetrazine sensitization, with supporting cytotoxicity and cell imaging. A bio-orthogonal click reaction between a Gd-tetrazine complex and a cyclic-RGD-norbornene conjugate was successful and the resulting clicked probe demonstrated enhanced relaxivity and could potentially act as a peptide shuttle for the Gd MRI agent.
血脑屏障阻碍了许多成像剂和治疗药物进入大脑，而这些药物本可用于对抗中枢神经系统疾病，如阿尔茨海默病和中风。然而，诸如使用环肽或肽穿梭体等技术可能会使有效载荷通过，通过生物正交的四嗪/降冰片烯点击化学实现生物缀合。本文已合成了一系列镧系四嗪探针，这些探针可用于与基于肽的递送系统进行生物正交点击化学，以通过血脑屏障递送磁共振成像（MRI）剂。在1.4 T时，钆配合物的弛豫率高于钆（DOTA）的临床标准，并且从铕和铽配合物中观察到四嗪敏化产生的磷光，同时具有支持性的细胞毒性和细胞成像。钆-四嗪配合物与环状RGD-降冰片烯共轭物之间的生物正交点击反应成功，所得的点击探针显示出增强的弛豫率，并有可能作为钆MRI剂的肽穿梭体。
