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Myocardial Kinetics of the ¹¹C-Labeled Enantiomers of the Ca²⁺ Channel Inhibitor S11568: An In Vivo Study

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

Ca²⁺ channels play a key role in the basic working of the heart. There is one particular type of Ca²⁺ channel in cardiac cells (L-type) whose gating is affected in different ways by ß-adrenoceptors and 1,4-dihydropyridines. In this study, we used ex vivo studies and PET to evaluate and compare the myocardial kinetics of the enantiomers labeled with ¹¹C (the more active: S12968, absolute configuration S; the less active: S12967, absolute configuration R) of the L-type Ca²⁺ channel antagonist S11568 (3-ethyl 5-methyl (±)-2-[(2-(2-aminoethoxy)ethoxy) methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate). Methods: [¹¹C]S12968 was injected into the tail vein of rats (0.22 kBq–5.92 MBq) to assess the relationship between injected dose and myocardial uptake. A series of 5 rats was pretreated with 4 µmol unlabeled S12968 5 min before injection of 2.2 kBq [¹¹C]S12968. In another series of 5 rats, unlabeled S12698 (4 µmol) was injected 5 min after injection of 2.2 kBq [¹¹C]S12968. The animals were killed 15 min later, and the myocardial radioactivity was assessed in a well counter. Beagle dogs received injections of 5–15 nmol [¹¹C]S12968 or [¹¹C]S12967 and were imaged with PET. Presaturation and displacement experiments using 2 µmol/kg unlabeled S12968 or 6 mol/kg S12967 were performed. Results: In rats, a statistically significant relationship between myocardial uptake and injected dose of S12968 was observed. Pretreatment or displacement with unlabeled S12968 reduced myocardial radioactivity by 75% and 70%, respectively. In dogs, after injection of 5 nmol of each enantiomer, myocardial radioactivity plateaued within 3 min and the clearance from blood was rapid. Injection of 13–15 nmol [¹¹C]S12968 led to a higher myocardial uptake and a more rapid washout, which were related to an increased coronary blood flow as shown by the linear relationship between k₁—an estimate of coronary blood flow—and the mass of S12968 injected. Presaturation and displacement experiments showed that 70%–80% of S12968 binding was specific. This specificity was not observed with S12967. Plasma metabolite analysis showed that 70% of the compound was unchanged 20 min after injection. Conclusion: These results show the feasibility of imaging myocardial L-type Ca²⁺ channels in vivo using [¹¹C]S12968.

Key Words: PET • heart • dihydropyridine binding • [¹¹C]S12968

This article has been cited by other articles:

				H. Valette, F. Dolle, I. Guenther, C. Fuseau, C. Coulon, F. Hinnen, J.-L. Peglion, and C. Crouzel In Vivo Quantification of Myocardial Dihydropyridine Binding Sites: A PET Study in Dogs J. Nucl. Med., September 1, 2002; 43(9): 1227 - 1233. [Abstract] [Full Text] [PDF]