Meyer Jan-Philip, Kozlowski Paul, Jackson James, Cunanan Kristen M, Adumeau Pierre, Dilling Thomas R, Zeglis Brian M, Lewis Jason S
Department of Radiology, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center , New York, New York 10065, United States.
J Med Chem. 2017 Oct 12;60(19):8201-8217. doi: 10.1021/acs.jmedchem.7b01108. Epub 2017 Sep 20.
Pretargeting offers a way to enhance target specificity while reducing off-target radiation dose to healthy tissue during payload delivery. We recently reported the development of an F-based pretargeting strategy predicated on the inverse electron demand Diels-Alder reaction as well as the use of this approach to visualize pancreatic tumor tissue in vivo as early as 1 h postinjection. Herein, we report a comprehensive structure: pharmacokinetic relationship study of a library of 25 novel radioligands that aims to identify radiotracers with optimal pharmacokinetic and dosimetric properties. This investigation revealed key relationships between molecular structure and in vivo behavior and produced two lead candidates exhibiting rapid tumor targeting with high target-to-background activity concentration ratios at early time points. We believe this knowledge to be of high value for the design and clinical translation of next-generation pretargeting agents for the diagnosis and treatment of disease.
预靶向提供了一种增强靶向特异性的方法，同时在递送有效载荷期间减少对健康组织的非靶向辐射剂量。我们最近报道了基于逆电子需求狄尔斯-阿尔德反应的基于氟的预靶向策略的开发，以及使用这种方法在注射后1小时就能够在体内可视化胰腺肿瘤组织。在此，我们报告了对25种新型放射性配体文库的全面结构-药代动力学关系研究，旨在鉴定具有最佳药代动力学和剂量学特性的放射性示踪剂。这项研究揭示了分子结构与体内行为之间的关键关系，并产生了两种先导候选物，它们在早期时间点表现出快速的肿瘤靶向性以及高的靶标与背景活性浓度比。我们认为这些知识对于设计用于疾病诊断和治疗的下一代预靶向剂以及临床转化具有很高的价值。
