A philosophy for CNS radiotracer design.
A philosophy for CNS radiotracer design.
复制标题
CNS Radiotracer设计的理念。
DOI：
10.1021/ar500233s
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发表时间：
2014-10-21
影响因子：
18.3
通讯作者：
Hooker, Jacob M.
中科院分区：
文献类型：
--
作者：
Van de Bittner, Genevieve C.;Ricq, Emily L.;Hooker, Jacob M.
正电子发射断层扫描（PET）被发现几十年后，它仍然是活体人类神经化学成像的首要工具。放射性标记方法、照相机设计和图像分析的技术改进使PET一直处于最前沿。此外，PET成像的使用已经扩大，因为研究人员已经开发出新的放射性示踪剂，可以可视化人脑内的受体，转运蛋白，酶和其他分子靶点。然而，在中枢神经系统（CNS）中的数千种蛋白质中，研究人员成功成像的人类蛋白质不到40种。为了满足对新放射性示踪剂的迫切需求，本报告根据我们在这一领域的现有经验，阐述了CNS放射性示踪剂开发的决策、策略和陷阱。我们讨论了五个关键组成部分的放射性示踪剂的发展为人类成像：选择一个生物医学问题，选择一个生物靶点，设计的放射性示踪剂的化学结构，候选放射性示踪剂的评价，和临床前成像分析。分析可能使用新放射性示踪剂的科学家或公司的市场并为该受众仔细选择相关的生物医学问题尤为重要。在选择一个特定的生物靶点，我们强调如何目标定位和身份可以约束这个过程，并讨论了最佳的目标密度和亲和力比所需的结合为基础的放射性示踪剂。此外，我们还讨论了各种PET测试-重测变异性要求，用于监测新放射性示踪剂的密度、占用率或功能变化。在新的放射性示踪剂结构的合成中，高通量、模块化合成已被证明是有价值的，并且这些过程为化合物提供了用于后期放射性同位素安装的位点。因此，研究人员可以管理与同位素有限半衰期相关的时间限制。为了评估脑摄取，有许多方法可用于预测生物利用度、血脑屏障（BBB）通透性以及非特异性结合和代谢稳定性的相关问题。为了评估合成的化学库，研究人员需要考虑高通量亲和测定，特异性结合的分析，以及快速结合动力学的重要性。最后，我们描述了我们如何初步评估临床前放射性示踪剂成像，使用脑摄取，特异性结合，和初步的动力学分析，以确定有前途的放射性示踪剂，可能是有用的人脑成像。虽然我们在本报告中单独和线性地讨论了这五个设计组件，但在实践中，我们使用这些设计组件非线性地和迭代地开发新的基于PET的放射性示踪剂，以尽可能有效的方式开发新化合物。
Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.
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影响因子：
3.7
作者：
Kamlet AS;Neumann CN;Lee E;Carlin SM;Moseley CK;Stephenson N;Hooker JM;Ritter T
通讯作者：
Ritter T
影响因子：
13.8
作者：
Pike VW
通讯作者：
Pike VW
影响因子：
15
作者：
Lee, Eunsung;Hooker, Jacob M.;Ritter, Tobias
通讯作者：
Ritter, Tobias
影响因子：
2.3
作者：
Narendran, Rajesh;Mason, N. Scott;Frankle, W. Gordon
通讯作者：
Frankle, W. Gordon
影响因子：
2.3
作者：
Biegon, Anat;Kim, Sung Won;Alexoff, David L.;Jayne, Millard;Carter, Pauline;Hubbard, Barbara;King, Payton;Logan, Jean;Muench, Lisa;Pareto, Deborah;Schlyer, David;Shea, Colleen;Telang, Frank;Wang, Gene-Jack;Xu, Youwen;Fowler, Joanna S.
通讯作者：
Fowler, Joanna S.