Department of Chemistry , University of Texas at Austin , Austin , Texas 78712-1224 , United States.
Acc Chem Res. 2020 Jan 21;53(1):2-10. doi: 10.1021/acs.accounts.9b00352. Epub 2019 Dec 6.
Fluorine magnetic resonance imaging (F MRI) is a promising bioimaging technique due to the favorable magnetic resonance properties of the F nucleus and the lack of detectable biological background signal. A range of imaging agents have been developed for this imaging modality including small molecule perfluorocarbons, fluorine-rich macromolecules and nanoparticles, and paramagnetic metal-containing agents. Incorporation of paramagnetic metals into fluorinated agents provides a unique opportunity to manipulate relaxation and chemical shift properties of F nuclei. Paramagnetic centers will enhance relaxation rates of nearby F nuclei through paramagnetic relaxation enhancement (PRE). Further, metals with anisotropic unpaired electrons can induce changes in F chemical shift through pseudocontact shift (PCS) effects. PRE and PCS are dependent on the nature of the metal center itself, the molecular scaffold surrounding it, and the position of the F nucleus relative to the metal center. One intriguing prospect in F magnetic resonance molecular imaging is to design responsive agents that can serve to provide a read out biological activity, including the activity of enzymes, redox activity, the activity of ions, etc. Paramagnetic agents are well suited for this activity-based sensing as metal complexes can be designed to respond to specific biological activities and give a corresponding F response that results from changes in the metal complex structure and subsequently PRE/PCS. Broadly speaking, when designing paramagnetic F MR biosensors, one can envision that in response to changes in analyte activity, the number of unpaired electrons of the metal changes or the ligand conformation/chemical composition changes. This Account highlights activity-based probes from the Que lab that harness paramagnetic metals to modulate F signal. We discuss probes that use conversion from Cu to Cu in response to reducing environments to dequench the F MR signal. Probes in which oxidants convert Co to Co, resulting in chemical shift responses, are also described. Finally, we explore our foray into using Ni coordination switching to furnish probes with different F signals when they are converted between 4-coordinate square planar and higher coordination numbers. A major barrier for F MR molecular imaging is in vivo application, as signal sensitivity is relatively low, requiring long imaging times to detect imaging agents. Nanoparticle and macromolecular agents show promise due to their higher fluorine density and longer circulation times; however, their analyte scope is limited to analytes that induce cleavage events. A grand challenge for researchers in this area is adapting lessons learned from small molecule paramagnetic probes with promising in vitro activities for the development of probes with enhanced in vivo utility for basic biological and clinical applications.
氟磁共振成像（F MRI）是一种很有前途的生物成像技术，因为氟核具有良好的磁共振性质，并且没有可检测到的生物背景信号。已经开发出一系列成像剂用于这种成像方式，包括小分子全氟碳化合物、富含氟的大分子和纳米颗粒以及含有顺磁金属的试剂。将顺磁金属掺入氟化剂中为氟核的弛豫和化学位移性质提供了独特的调节机会。顺磁中心通过顺磁弛豫增强（PRE）来增强附近氟核的弛豫率。此外，具有各向异性未配对电子的金属可以通过赝接触位移（PCS）效应引起氟化学位移的变化。PRE 和 PCS 取决于金属中心本身的性质、围绕它的分子支架以及氟核相对于金属中心的位置。氟磁共振分子成像中一个有趣的前景是设计响应性试剂，这些试剂可以提供生物活性的读出，包括酶的活性、氧化还原活性、离子的活性等。顺磁试剂非常适合这种基于活性的传感，因为可以设计金属配合物来响应特定的生物活性，并产生相应的 F 响应，这是由金属配合物结构的变化以及随后的 PRE/PCS 引起的。广义地说，在设计顺磁 F MR 生物传感器时，可以设想，由于分析物活性的变化，金属的未配对电子数或配体构象/化学成分发生变化。本综述突出了 Que 实验室基于顺磁金属来调节 F 信号的基于活性的探针。我们讨论了使用从 Cu 到 Cu 的转化来响应还原环境以去猝灭 F MR 信号的探针。还描述了其中氧化剂将 Co 转化为 Co，导致化学位移响应的探针。最后，我们探索了我们使用 Ni 配位开关的尝试，当它们在 4 配位平面四方和更高的配位数之间转换时，为具有不同 F 信号的探针提供不同的 F 信号。F MR 分子成像的一个主要障碍是体内应用，因为信号灵敏度相对较低，需要较长的成像时间来检测成像剂。纳米颗粒和大分子试剂由于其较高的氟密度和较长的循环时间而显示出前景；然而，它们的分析物范围仅限于诱导裂解事件的分析物。该领域研究人员的一个重大挑战是从具有有前途的体外活性的小分子顺磁探针中吸取经验教训，为基本生物学和临床应用的体内应用增强探针的开发。
