TY - JOUR
T1 - Concepts for design and analysis of receptor radiopharmaceuticals
T2 - The Receptor-Binding Radiotracers series of meetings provided the foundation
AU - Krohn, Kenneth A.
AU - Vera, David R.
N1 - Funding Information:
It would be impossible to list all the mentors from whom we have developed the perspectives we have described. However, a few individuals stand above the many participants in the four Receptor Radiopharmaceuticals Workshops. The two we would like to mention are Bill Eckelman and Paul Schiebe. We have also benefitted from generous NIH, DOE, and DOD support over several decades and an ICMIC from the NCI Cancer Imaging Program. We thank Nihon Mediphysics for taking the chance to commercialize Tc-GSA. P01 CA042045, which extended over three decades, was particularly important in developing the concepts described here, including teaching them to numerous young investigators who have been successful in developing new imaging agents.
Publisher Copyright:
© 2020
PY - 2021/1
Y1 - 2021/1
N2 - 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 KD, 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′max into the true second-order rate constant, k3, 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.
AB - 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 KD, 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′max into the true second-order rate constant, k3, 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.
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U2 - 10.1016/j.nucmedbio.2020.03.002
DO - 10.1016/j.nucmedbio.2020.03.002
M3 - Review article
C2 - 32331709
AN - SCOPUS:85083501168
VL - 92
SP - 5
EP - 23
JO - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
JF - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
SN - 0969-8051
ER -