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Basic Science Investigations |
1 Service Hospitalier Frédéric Joliot, Commissariat à l’Energie Atomique/Direction des Sciences du Vivant, Orsay, France
2 Merck–Lipha, Centre de Recherche de Chilly-Mazarin, Chilly-Mazarin, France
Previous studies showed that the in vivo concentration of ß-adrenergic receptor sites can be estimated by PET using (-)-4-((S)-3-tert-butylamino-2-hydroxypropoxy)-1,3-dihydrobenzoimidazol-2-one (CGP 12177), a hydrophilic ligand. A graphic method was previously proposed and used by several groups. However, this approach was not completely validated. The purpose of this study was to improve and confirm the validity of this approach through a better knowledge of the associated ligand-receptor model, estimated for the first time using the multiinjection approach. Methods: The concentration of ß-adrenergic receptor sites was estimated for mini pigs using 2 methods. The first was the usual multiinjection approach, which permits estimation of all model parameters, including receptor concentration. However, this approach needs a complex protocol, including blood sampling, thereby making it difficult to use for studies on patients. The second method was the CGP 12177 graphic method. This approach permits the estimation of only receptor concentration but has the advantage of not requiring blood sampling. Another advantage is the ability to generate parametric images easily. Results: Using the multiinjection approach, we obtained for the first time a complete model describing interactions between CGP 12177 and ß-adrenergic receptors. Knowledge of all parameters of this model permitted good validation of the assumptions included in the graphic method. The concentration of ß-adrenergic receptor sites in mini pigs was estimated at 15.2 ± 3.4 pmol/mL. Conclusion: The graphic method has been improved by taking into account various phenomena, such as protein binding and the nonlinearity between plasma concentration and injected dose. This method is now usable for patient studies and offers the ability to estimate the ß-adrenergic receptor concentration from a single PET experiment without blood sampling. Parametric imaging will enable screening of the receptor site location and observation of potential anomalies in patients.
Key Words: (-)-4-((S)-3-tert-butylamino-2-hydroxypropoxy)-1,3-dihydrobenzoimidazol-2-one (CGP 12177) • ß-adrenergic receptors • ligand-receptor modeling • parametric imaging
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