Santosh S. Arcot, PhD., Marketing Manager and Martin Cordell, PhD., Product Manager, Siemens Healthcare
Drug Discovery & Development - March 09, 2010
As is common in all drug discovery and development projects, upon the identification of promising lead compounds, the next steps usually involve initial safety tests in animal subjects. As part of these safety tests, scientists evaluate ADME properties or “pharmacokinetics” of each lead compound. In order to proceed to the next phase, candidates must demonstrate that they are absorbed into the bloodstream, distributed to the proper site of action, metabolized efficiently and effectively, and then excreted from the body.
In vivo imaging techniques such as positron emission tomography (PET) provide a means to perform dynamic ADME studies in mouse models without sacrificing the animal..Despite this benefit, live-animal pharmacokinetic studies of cardiac drugs pose a unique challenge in mice. A typical mouse heart rate is between 300-500 beats/min, making it very challenging to perform accurate pharmacokinetic studies using dynamic imaging techniques due to the motion artifacts produced.
With the introduction of dual-gated dynamic imaging technique, it is now possible to obtain high-resolution PET images of “motion-frozen” time points in an ADME study and be able to quantify the amount of drug in the target organ of interest.
How does “dual-gated” dynamic PET imaging work?Physiological motion in a mouse cardiac study is the result of the heart beating and respiratory motion. PET imaging is most effective if motion artifacts can be filtered out. This is typically performed by using physiological monitoring equipment to introduce “gating” tags to the raw PET acquisition data (also referred to as list mode data), indicating the start of the cardiac and respiratory cycles.
The first panel in the figure depicts the introduction of cardiac and respiratory tags into the list mode data (Step 1). Upon the completion of the study, the list mode data is then retrospectively processed by subdividing the data into a number of images to show the uptake of the compound over time and at different phases of the physiological cycles. The second panel in the figure shows how the time and gating tags allow the user to define the length of each dynamic frame as well as the number of bins for each physiological process (Step 2). Selected images from the various frames in a dynamic study can be subjected to further analysis. The third panel highlights the ability to select a single phase of the physiological cycle for analysis, effectively freezing the physiological motion and eliminating the motion-blurring effects. Regions of interest can then be accurately defined on the images and the data can be quantified for the presence of the experimental labeled drug. This data can then be plotted as time-activity curves and kinetic modeling functionality can be used to calculate the rate of drug uptake (Step 3).
This technique offers several benefits. It allows the use of mice as animal models— without sacrificing large number of subjects—thereby reducing costs. The continued survival, and therefore analysis, of the subject animal minimizes variability and ensures accuracy of data. Lastly, PET imaging provides for measuring rapid kinetics and can therefore generate a more accurate picture of the ADME process.
In vivo imaging techniques such as positron emission tomography (PET) provide a means to perform dynamic ADME studies in mouse models without sacrificing the animal..Despite this benefit, live-animal pharmacokinetic studies of cardiac drugs pose a unique challenge in mice. A typical mouse heart rate is between 300-500 beats/min, making it very challenging to perform accurate pharmacokinetic studies using dynamic imaging techniques due to the motion artifacts produced.
With the introduction of dual-gated dynamic imaging technique, it is now possible to obtain high-resolution PET images of “motion-frozen” time points in an ADME study and be able to quantify the amount of drug in the target organ of interest.
How does “dual-gated” dynamic PET imaging work?Physiological motion in a mouse cardiac study is the result of the heart beating and respiratory motion. PET imaging is most effective if motion artifacts can be filtered out. This is typically performed by using physiological monitoring equipment to introduce “gating” tags to the raw PET acquisition data (also referred to as list mode data), indicating the start of the cardiac and respiratory cycles.
The first panel in the figure depicts the introduction of cardiac and respiratory tags into the list mode data (Step 1). Upon the completion of the study, the list mode data is then retrospectively processed by subdividing the data into a number of images to show the uptake of the compound over time and at different phases of the physiological cycles. The second panel in the figure shows how the time and gating tags allow the user to define the length of each dynamic frame as well as the number of bins for each physiological process (Step 2). Selected images from the various frames in a dynamic study can be subjected to further analysis. The third panel highlights the ability to select a single phase of the physiological cycle for analysis, effectively freezing the physiological motion and eliminating the motion-blurring effects. Regions of interest can then be accurately defined on the images and the data can be quantified for the presence of the experimental labeled drug. This data can then be plotted as time-activity curves and kinetic modeling functionality can be used to calculate the rate of drug uptake (Step 3).
This technique offers several benefits. It allows the use of mice as animal models— without sacrificing large number of subjects—thereby reducing costs. The continued survival, and therefore analysis, of the subject animal minimizes variability and ensures accuracy of data. Lastly, PET imaging provides for measuring rapid kinetics and can therefore generate a more accurate picture of the ADME process.
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