设计合成基于19F磁共振成像检测蛋白酶活性的探针

19F magnetic resonance imaging (19F MRI) is a promising moiety for quantitative MRI and is receiving more and more attention due to its high spatial resolution, deep tissue penetration and good soft tissue contrast, and non-invasive assessment of tissue anatomy, physiology and pathology. Although 19F MR is only four years younger than 1H MRI, it is not in clinical use. The progress of 19F MRI has been stalled by the lack of suitable imaging agents. Current 19F imaging agents are most based on perfluorocarbon emulsions and suffer severe shortcomings, including instability, split 19F signal, complex formulation procedure and excessive retention of the agents in organs for a long time. Based on our pilot work on 19F imaging agents, we try to design and synthesis of a series of spherical symmetric fluorine dendrons, which exhibit strong and single 19F signal with high fluorine content, the newly designed probe may overcome the major deficiencies of perfluorocarbon based imaging agents. The dendrons can be conveniently conjugated to protease substrates via modification. Upon treatment with protease, the probe will be cleaved and 19F signal will be released, the enhanced 19F signal can be monitored by 19F magnetic resonance spectroscopy or MRI. The probe will be evaluated of real time imaging of enzyme activities in vivo, offering valuable information in understand the occurrence and progress of the disease in molecular level. In conjunction with rapid improvements in 19F MRI, the prospects for early topical, qualitative and quantitative treatment of disease, development of personalized medicine have never been better.

19F MR成像的高空间分辨率，无限的穿透深度和良好的软组织对比，同时可无损伤获得三维解剖结构及生理信息而受到越来越广泛的关注。19F MR成像的研究相比1H成像只晚四年时间，但至今19F MR成像并没有用于临床，其中原因之一是目前主要基于全氟碳乳液的磁共振成像试剂普遍存在不稳定、19F 信号裂分、复杂的配方制备过程、容易在体内残留等诸多不足。申请人在前期基于19F MR分子影像剂的基础上，设计合成一类具有高度对称高氟含量的合成子，该合成子经过修饰连接到蛋白酶专一识别的底物中的中并改变其磁共振参数，在蛋白酶的作用下探针被激发并释放19F信号， 相应信号通过磁共振频谱和磁共振成像得到反馈，该探针有望用于活体内实时监控酶活性，为以分子水平对疾病诊断提供定位、定性、定量和对疾病分期的准确依据，探索高效并具有个性化的诊疗剂。

生物医学科技的发展对疾病的诊断起到非常重要的作用，越来越多的影像学方法用于疾病的诊断，尤其在分子水平针对疾病的诊断能提供定位、定性、定量和对疾病分期的准确依据，因此影像学探针开发是一个很有价值的研究议题。设计并合成高效、专一、非侵袭性的影像学探针用于分子水平活体内监测成为疾病诊断发展的趋势。而19F MR成像的高空间分辨率，无限的穿透深度和良好的软组织对比，同时可无损伤获得三维解剖结构及生理信息也受到越来越广泛的关注。本课题在项目基金资助下已经设计并合成了一类具有高度对称高氟含量的19F探针F9-PEG-Mal-PEP-DOTA-Gd，该探针对肿瘤组织中高度表达的基质金属蛋白酶（MMP）具有特异性，易于修饰且具有良好生物相容性。在蛋白酶的作用下探针被激发并释放19F信号，相应信号通过磁共振频谱和磁共振成像可得到反馈。随后，本课题在此基础上进行了相关的动物实验研究，并增加了19F 探针在脑损伤中的应用。在外伤性脑损伤模型上，可以明确观察到19F信号的蓄积。经过修饰，该类19F探针有望用于活体内实时监控酶活性,有利于高效且个体化的疾病诊断。