Fluorine-18 Ligands for the in Vivo Study of the Beta Adrenergic Receptor in the Heart and Lung
In the last 10 years there has been considerable interest in development of receptor ligands labeled with externally detectable radionuclides for the study of receptors in vivo. Most of the interest has been directed towards compounds labeled with positron emitting radionuclides permitting in vivo studies to be performed using positron emission tomography (PET) and the majority of studies have been directed towards the brain. One of the challenges in all in vivo receptor ligand studies is the estimation of non-specific binding, normally measured in vitro by as that binding which occurs in the presence of a large excess of ligand. In studies in the brain the non-specific binding of the ligand is typically estimated by finding an area of the brain that has the same or similar blood flow and partition coefficient as the area of interest but has none of the receptors of interest. This tissue can then be used to estimate the amount of non-specific binding of the ligand, which can be subtracted from the activity in the area of interest to give the specific binding. However, if the area of interest is in the heart and lung such a method is not applicable since there is no tissue in the field of view with similar properties but no receptors to provide the non-specific measurement. To distinguish the nonspecific from the specific binding in such cases it is necessary to use the kinetics of the two processes to separate them. Thus the non-specific binding is rapid and independent of the ligand and we can assume that the non-specifically bound tracer in the tissue and the tracer in the blood will be in equilibrium, even though the concentration of the tracer in the blood will be constantly changing. On the other hand the ligand-receptor interactions are slower, especially the disassociation of the ligand-receptor complex. To use this kinetic difference to distinguish between specific and the non-specific binding, the dissociation of the ligand receptor complex must be as slow as possible and the system must be observed for a sufficient length of time to measure changes in all the processes. The time period involved will depend upon the ligand, not only in its kinetics of binding to the receptor, but also in its blood-tissue partition coefficient which dictates the time scale of the nonspecific binding changes. Although the time scale can only be approximated ahead of time it can be estimated to be in hours. Of the available PET radionuclides only fluorine-18 has a long enough half-life to meet these requirements.
KeywordsPositron Emission Tomography Partition Coefficient Indole Derivative Phenyl Hydrazones Ligand Receptor Complex
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