The in Vivo Quantification of the Receptor Site Concentration Using Ligand-Receptor Interaction Modeling
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Drug I n f o m i o n Journal. Vol. 31. pp. 1019-1027. 1997 Printed in the USA. All rights reserved.
THE IN VIVO QUANTIFICATION OF THE RECEPTOR SITE CONCENTRATION USING LIGAND-RECEPTOR INTERACTION MODELING JACQUES DELFORGE, PHD Commissariat A 1’Energie Atomique, Service Hospitalier F. Joliot, Hopital d’Orsay, Orsay, France
The in vivo quantification of receptor concentration and ligand ajfinity, using data obtained with positron emission tomography, is based on a compartmental analysis of the ligand-receptor interactions. To investigate the afinity of drugs for the receptor sites o d o r the possible alterations in various diseases of the receptor concentrations or of the drug interactions, many methods for quantitatively measuring the binding parameters have been devised. Key Words: Receptor; Ligand; Affinity; Positron emission tomography; Modeling; Lipophilicity
WITH THE ADVENT OF positron emission tomography (PET) and the recent development of specific ligands labeled with shortlived positron emitters, it is now possible to study in vivo in humans the interactions between ligands and receptor sites. One of the challenges is the quantification from PET data of the receptor site density and of the ligand affinity for these receptor sites. Such quantitative analysis is essential for the understanding of the pharmacological properties of the endogeneous ligands and the role of the binding sites in normal or pathological conditions. PET measures the labeled ligand concentration in a region of interest, but it does not allow the direct measurement of the receptor concentration and the ligand affinity. To esti~~~
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Presented at the DIA Workshop “Positron Emission Tomography (PJX),” November 20-21, 1995, Bruges, Belgium. Reprint address: Jacques Delforge. PhD. Commissariat A 1’Energie Atomique, Service Hospitaher F. Joliot, Hopital &Orsay, Orsay, France 91406.
mate these parameters, a mathematical model must be devised to simulate the kinetic of the labeled molecule in the tissue. These physiological parameters will appear as model parameters which have to be identified from the experimental PET curves, often simultaneously with other model parameters (usually kinetic rate constants).
THE LIGAND-RECEITOR MODEL Model Structure Several models have recently been proposed as a framework for the analysis and quantification of ligand-receptor interactions investigated in vivo from PET data (1-7). The complexity of the model, that is to say of the simulated physiological process, varies a great deal, depending on the organ, the tracer used, the receptor type, and the available experimental data. All the in vivo approaches are based on a mathematical model which includes at least two steps:
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Jacques Dclforgc
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1. A transport of the ligand from the blood
to a free ligand compartment (a necessary step since the labeled ligand is injected intravenously), and 2. A classical ligand-receptor interaction similar to that used in in v i m studi
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