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

Journal of Nuclear Medicine

Héric Valette¹  Christine Coulon¹  Françoise Hinnen¹  Chantal Fuseau¹  Jean-Louis Péglion¹  Ilonka Guenther¹  Frédéric Dollé¹  Christian Crouzel¹ 

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

关键词: PET;    heart;    dihydropyridine binding;    [¹¹C]S12968;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 β-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 γ 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 k1an estimate of coronary blood flowand 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.

【 授权许可】

Unknown