Myocardial kinetics of the (11)C-labeled enantiomers of the Ca(2+) channel inhibitor S11568: an in vivo study.
Ca(2+) channels play a key role in the basic working of the heart. There is one particular type of Ca(2+) channel in cardiac cells (L-type) whose gating is affected in different ways by beta-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 (11)C (the more active: S12968, absolute configuration S; the less active: S12967, absolute configuration R) of the L-type Ca(2+) 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
[(11)C]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 micromol unlabeled S12968 5 min before injection of 2.2 kBq [(11)C]S12968. In another series of 5 rats, unlabeled S12698 (4 micromol) was injected 5 min after injection of 2.2 kBq [(11)C]S12968. The animals were killed 15 min later, and the myocardial radioactivity was assessed in a gamma well counter. Beagle dogs received injections of 5-15 nmol [(11)C]S12968 or [(11)C]S12967 and were imaged with PET. Presaturation and displacement experiments using 2 micromol/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 [(11)C]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 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 specificity was not observed with S12967. Plasma metabolite analysis showed that 70% of the compound was unchanged 20 min after injection.


CONCLUSIONS
These results show the feasibility of imaging myocardial L-type Ca(2+) channels in vivo using [(11)C]S12968.
Valette
H
H
Service Hospitalier Frédéric Joliot, Direction of Life Sciences, Department of Medical Research, French Atomic Agency, Orsay, France.
Dollé
F
F
Guenther
I
I
Hinnen
F
F
Fuseau
C
C
Coulon
C
C
Péglion
J L
JL
Crouzel
C
C
D000818:Animals; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003326:Coronary Circulation; D004095:Dihydropyridines / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D004095:Dihydropyridines; C067838:S 11568