Highly efficient synthesis of [C-11]S12968 and [C-11]S12967, for the in vivo imaging of the cardiac calcium channels using PET

The dihydrophyridines S12968 ((-)-S11568, absolute configuration S) and S12 967 ((+)-S11568, absolute configuration R), 3-ethyl 5-methyl (-/+)-2-[(2(2- aminoethoxy)ethoxy)methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydro-pyri dine-3, 5-dicarboxylate, have both an in vitro profile of high potency and of high selectivity for the low-voltage-dependent L-type calcium channel. I n this paper, the radiosynthesis of both enantiomers, S12968 and S12967, wi th carbon-11, a positron-emitting isotope (half-life:20.4 min) was investig ated and oriented towards the preparation of multi milliCuries of radiotrac er. Typically, 130-250 mCi (4.81-9.25 GBq) of [C-11]S12968 and [C-11]S12967 were obtained within 30min of radiosynthesis (HPLC purification included) with specific radioactivities ranging from 500 to 1000mCi/mu mol (18.5-37.0 GBq/ mu mol) using no-carrier-added [C-11]methyl triflate as the alkylatin g agent and the appropriate, enantiomerically pure carboxylic acid precurso r at 100 degreesC for 1 min. Based on preliminary PET experiments, only the levo enantiomer S12968 ((-)-[C-11]-1) appears to be suitable for myocardia l PET imaging as demonstrated in vivo in beagle dogs: with S12968, 85% of t he uptake of [C-11]S12968 could be inhibited in pretreatment experiments an d up to 70% of [C-11]S12968 could be displaced. Further investigations are currently underway in order to provide an absolute quantification of ventri cular calcium channels with PET. Copyright (C) 2001 John Wiley & Sons, Ltd.