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In Vivo Quantification of Myocardial Dihydropyridine Binding Sites: A PET Study in Dogs

¹ Department of Medical Research, Direction of Life Sciences, Service Hospitalier Frédéric Joliot, French Atomic Agency, Orsay, France
² Institut de Recherche Servier, Suresnes, France

Abnormalities in myocardial L-type Ca²⁺ channel abundance and function have been described in cardiac hypertrophy and failure. In vivo quantification of the density of these channels using PET and an adequate ligand would provide new insights into cardiac disease. Methods: The dihydropyridine L-type Ca²⁺ channel antagonist S12968 (3-ethyl 5-methyl (-)-2-[(2-(2-aminoethoxy)ethoxy)methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate) was labeled with ¹¹C and injected in various amounts (5–23 nmol), 20 or 30 min apart, into dogs. This protocol allowed a separate evaluation of the density of binding sites (B_max) as well as association and dissociation rate constants. The parameters were calculated using a nonlinear mathematic model. Results: Using the multiinjection approach, a complete model describing interactions between S12968 and the dihydropyridine binding sites was obtained. B_max was found to be 19.2 ± 3.3 pmol·mL^-1 of tissue. Association and dissociation constants (estimated by K_on/VR and K_dVR, respectively) were found to be 0.015 ± 0.01 mL·pmol^-1·min^-1 and 4.2 ± 2.2 nmol·mL^-1, respectively. Conclusion: The present data suggest that it is possible to measure myocardial dihydropyridine binding site density with a single radiosynthesis and a simple PET protocol that is not time consuming (75 min for the total examination, including transmission and emission scans). This methodology can be useful to investigate human cardiac disease in vivo.

Key Words: PET • heart • dihydropyridine binding • ¹¹C-S12968