Stewart Rachel C, Patwa Amit N, Lusic Hrvoje, Freedman Jonathan D, Wathier Michel, Snyder Brian D, Guermazi Ali, Grinstaff Mark W
Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University , 590 Commonwealth Ave., Boston, Massachusetts 02215, United States.
Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center and Harvard Medical School , 1 Overland Street, RN 115, Boston, Massachusetts 02215, United States.
J Med Chem. 2017 Jul 13;60(13):5543-5555. doi: 10.1021/acs.jmedchem.7b00234. Epub 2017 Jun 27.
Contrast agents that go beyond qualitative visualization and enable quantitative assessments of functional tissue performance represent the next generation of clinically useful imaging tools. An optimized and efficient large-scale synthesis of a cationic iodinated contrast agent (CA4+) is described for imaging articular cartilage. Contrast-enhanced CT (CECT) using CA4+ reveals significantly greater agent uptake of CA4+ in articular cartilage compared to that of similar anionic or nonionic agents, and CA4+ uptake follows Donnan equilibrium theory. The CA4+ CECT attenuation obtained from imaging ex vivo human hip cartilage correlates with the glycosaminoglycan content, equilibrium modulus, and coefficient of friction, which are key indicators of cartilage functional performance and osteoarthritis stage. Finally, preliminary toxicity studies in a rat model show no adverse events, and a pharmacokinetics study documents a peak plasma concentration 30 min after dosing, with the agent no longer present in vivo at 96 h via excretion in the urine.
超越定性可视化并能够对功能性组织性能进行定量评估的造影剂代表了下一代具有临床实用价值的成像工具。本文描述了一种用于关节软骨成像的阳离子碘化造影剂（CA4+）的优化高效大规模合成方法。使用CA4+的对比增强CT（CECT）显示，与类似的阴离子或非离子造影剂相比，关节软骨对CA4+的摄取明显更高，并且CA4+的摄取遵循唐南平衡理论。从离体人髋关节软骨成像获得的CA4+ CECT衰减与糖胺聚糖含量、平衡模量和摩擦系数相关，这些是软骨功能性能和骨关节炎阶段的关键指标。最后，在大鼠模型中的初步毒性研究未显示不良事件，药代动力学研究记录了给药后30分钟的血浆浓度峰值，96小时后该造影剂通过尿液排泄不再存在于体内。
