Canine myocardial dihydropyridine binding sites: a positron emission tomographic study with the calcium channel inhibitor 11C-S11568.
The in vivo determination of the density of dihydropyridine (DHP) binding sites will allow the assessment of pathophysiological changes associated with heart disease. The calcium channel antagonist S 11568: (+/-)(amino-7 dioxa-2,5 heptyl)-2(dichloro -2,3 phenyl) -4 methyl-6dihydro -1,4 pyridine has an in vitro profile of high potency and of high selectivity for the L-type Ca2+ channel. S 11568 was labelled by a reaction between 11C-diazomethane and the precursor 6-(7-amino-2,5-dioxa heptyl)-4-(2,3-dichloro phenyl)-5-(ethoxycarbonyl)-2 methyl-1,4 dihydro nicotinic acid. (+)-PN 200 110, a DHP with in vitro high affinity for the L-type Ca2+ channel, was also radiolabeled. Positron emission tomographic (PET) studies of both 11C-DHP myocardial uptake were performed in Beagle dogs. 11C-(+)-PN 200 110 had a rapid wash-out from myocardium. In contrary, after a bolus injection, 11C-S 11568 myocardial concentration increased to reach a maximum in 1-2 minutes and then remained in a plateau with a slight downslope while the blood concentration fell rapidly. Myocardial uptake was 2 to 4 fold higher than lung uptake, leading to a good contrast on PET images. Pre-treatment with unlabeled S 11568 (2 mumol/kg or 6 mumol/kg over 15 minutes) reduced myocardial uptake by 60% and 80%, respectively. Specific binding was estimated during a displacement experiment: bolus of unlabeled S 11568: 1 mumol/kg followed by a continuous infusion of 3 mumol/kg over 2 hours. It was found to represent 80% of the total binding. To assess influence of S 11568 on coronary blood flow and therefore on the myocardial tracer delivery, coronary blood flow was measured using 15O-H2O and PET at baseline and following bolus injections of 0.4, 0.8, 2 mumol/kg of S 11568. Only the higher dose increased coronary blood flow. This is the in vivo demonstration of the binding characteristics to myocardial tissue of a DHP ligand. Such properties make S 11568 suitable for PET experiments. The studies of DHP binding sites will provided new insights concerning physiological situations as well as heart disease.
Service Hospitalier Frédéric Joliot, DRIPP-CEA, Orsay, France.
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D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000187:drug effects; D004095:Dihydropyridines / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D017275:Isradipine / Q000493:pharmacokinetics; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D014055:Tomography, Emission-Computed
D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D004095:Dihydropyridines; C067838:S 11568; C038806:1,4-dihydropyridine; D017275:Isradipine