Myocardial kinetics of the C-11-labeled enantiomers of the Ca2+ channel inhibitor S11568: An in vivo study

Ca2+ channels play a key role in the basic working of the heart. There is o ne particular type of Ca2+ channel in cardiac cells (L-type) whose gating i s affected in different ways by p-adrenoceptors and 1,4-dihydropyridines In this study, we used ex vivo studies and PET to evaluate and compare the my ocardial kinetics of the enantiomers labeled with C-11 (the more active: S1 2968, absolute configuration S; the less active: S12967, absolute configura tion 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-,4-d ihydropyridine-3,5-dicarboxylate), Methods: [11C]S12968 was injected into t he 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 wit h 4 mu mol unlabeled S12968 5 min before injection of 2.2 kBq [C-11]S12968. In another series of 5 rats, unlabeled S12698 (4 mu mol) was injected 5 mi n after injection of 2.2 kBq [C-11]S12968. The animals were killed 15 min l ater, and the myocardial radioactivity was assessed in a gamma well counter . Beagle dogs received injections of 5-15 nmol [C-11]S12968 or [C-11]S12967 and were imaged with PET. Presaturation and displacement experiments using 2 mu mol/kg unlabeled S12968 or 6 mol/kg S12967 were performed. Results: I n rats, a statistically significant relationship between myocardial uptake and injected dose of S12968 was observed. Pretreatment or displace ment wit h unlabeled S12968 reduced myocardial radioactivity by 75% and 70%, respect ively. In dogs, after injection of 5 nmol of each enantiomer, myocardial ra dioactivity plateaued within 3 min and the clearance from blood was rapid. Injection of 13-15 nmol [C-11]S12968 led to a higher myocardial uptake and a more rapid washout, which were related to an increased coronary blood flo w as shown by the linear relationship between k(1)-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 specif icity 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 [C-11]S12968.