SYNTHESIS OF 2 OPTICALLY-ACTIVE CALCIUM-CHANNEL ANTAGONISTS LABELED WITH C-11 FOR IN-VIVO CARDIAC PET IMAGING

(+/-)-S11568 (1, oethoxy)methyl]-4-(2,3-dichlorophenyl)-6-methyl-1, 4- dihydropyridine -3,5-dicarboxylate), has an in vitro profile of high p otency and of high selectivity for the low-voltage dependent L-type ca lcium channel. In in vitro binding studies, it displaced specifically bound (-)-[H-3]PN 200-110 (isradipine (2), the reference molecule for in vitro studies) from cardiac and vascular smooth muscle preparations with potencies of 5.6 and 51 nM, respectively. It also appears as a p ure pharmacological antagonist acting at a single channel L-type and f ree of any interaction at the benzothiazepine binding site such as aml odipine (3). Both enantiomers of S11568 have in vitro activities, the dextro isomer S12967 ((+)-1) being 6 to 18-fold less potent than the l evo one S12968 ((-)-1). Two couples of optically active labelling prec ursors of S11568, ((-)-10/(+)-10 and (-)-14/(+)-14) have been synthesi zed using a modified Hantzsch's dihydropyridine synthesis. In both cas es, the enantiomers were separated by preparative chiral HPLC. They bo th have been independently labelled with carbon-ii, using [C-11]diazom ethane or [C-11]iodomethane to give multimilliCurie quantities of (-)- 1 (S12968) and (+)-1 (S12967) with high specific activities (500-1000 mCi/mu mol, 18.5-37.0 GBq/mu mol). Both enantiomers appear suitable fo r PET experiments: their myocardial concentration increases after a bo lus injection to reach a maximum in 2 min and then remains on a platea u with a slight downslope while the blood concentration falls rapidly. Myocardial uptake was threefold higher than lung uptake, leading to a good contrast on PET images. The present preliminary biological resul ts obtained in Beagle dogs showed that both enantiomers have similar m yocardial kinetics and in vivo affinity for the left ventricular myoca rdium. (C) 1997 Elsevier Science Ltd.