Center for Radiochemistry Research, Department of Diagnostic Radiology, Mail Code L104, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America.
UCSD Moores Cancer Center, Department of Radiology, Mail Code 0819, University of California, San Diego, CA 92037, United States of America.
Nucl Med Biol. 2021 Jan;92:5-23. doi: 10.1016/j.nucmedbio.2020.03.002. Epub 2020 Mar 12.
A symposium at George Washington University on Receptor-Binding Radiotracers in 1980 and three follow-up meetings held at University of California, San Diego provided a forum for debating the critical concepts involved in the new field of designing and evaluating radiotracers for imaging receptors and transporters. This review is intended to educate young investigators who may be relatively new to receptor radiopharmaceutical development. Our anticipated audience includes researchers in basic pharmacology, radiochemistry, imaging technology and kinetic data analysis and how these disciplines have worked together to build our understanding of the human biology of transporters and receptor signaling in health and disease. We have chosen to focus on radiochemical design of a useful imaging agent and how design is coupled to analysis of data collected from dynamic imaging with that agent. Some pharmacology may be required for designing the imaging agent and some imaging physics may be important in optimizing the quality of data that is collected. However, the key to a successful imaging agent is matching the radiotracer to the target receptor and to analysis of the time-course data that is used to parse delivery from specific binding and subsequent metabolism or degradation. Properly designed imaging agents are providing critical information about human biology in health and disease as well as pharmacodynamic response to drug interventions. The review emphasizes some of the ideas that were controversial at the 1980 conference and chronicles with literature examples how they have resolved over the four decades of using radiotracers to study transporters and receptors in human subjects. These examples show that there are situations where a very small K, i.e. high affinity, has the potential to yield an image that reflects blood flow more than receptor density. The examples also show that by combining two studies, one with high specific activity and a second with low specific activity injections one can unravel the pseudo-first order rate B' into the true second-order rate constant, k, and the unoccupied receptor density. The final section describes how mathematical methods first presented to the receptor-imaging community in 1980 are now being used to provide confidence in the analysis of kinetic biodistribution studies. Our hope is that by bringing these concepts together in a single review, the next generation of scientists developing receptor imaging agents can be much more efficient than their pioneers in developing useful imaging methods.
1980 年，乔治华盛顿大学举办了一场关于受体结合放射性示踪剂的研讨会，随后在加利福尼亚大学圣地亚哥分校又举办了三次后续会议，为讨论设计和评估用于成像受体和转运体的放射性示踪剂的新领域所涉及的关键概念提供了一个论坛。本综述旨在为可能对受体放射性药物开发相对较新的年轻研究人员提供教育。我们的预期受众包括基础药理学、放射化学、成像技术和动力学数据分析方面的研究人员，以及这些学科如何共同努力，加深我们对健康和疾病中转运体和受体信号的人类生物学的理解。我们选择专注于有用成像剂的放射化学设计，以及如何将设计与从该示踪剂的动态成像中收集的数据进行分析相结合。设计成像剂可能需要一些药理学知识，而优化所收集数据的质量可能需要一些成像物理学知识。然而，成功的成像剂的关键是将放射性示踪剂与目标受体相匹配，并对用于解析递送至特异性结合以及随后的代谢或降解的时间过程数据进行分析。适当设计的成像剂正在为健康和疾病中的人类生物学以及药物干预的药效动力学反应提供关键信息。本综述强调了 1980 年会议上有争议的一些观点，并通过文献实例记录了在使用放射性示踪剂研究人体中的转运体和受体的四十年中，这些观点是如何得到解决的。这些例子表明，在某些情况下，K，即高亲和力，非常小，有可能产生比受体密度更能反映血流的图像。这些例子还表明，通过结合两项研究，一项具有高比活度，另一项具有低比活度注射，可以将伪一级速率 B'分解为真实的二级速率常数 k 和未占据的受体密度。最后一部分描述了 1980 年首次向受体成像社区提出的数学方法如何用于为动力学生物分布研究的分析提供信心。我们希望，通过将这些概念汇集在一篇综述中，开发受体成像剂的下一代科学家能够比他们的先驱在开发有用的成像方法方面更加高效。
