SYNTHESIS AND CHARACTERIZATION OF A C-11 LABELED DERIVATIVE OF S12968- AN ATTEMPT TO IMAGE IN-VIVO BRAIN CALCIUM CHANNELS

[C-11]S11568 (3-ethyl 5-methyl 2-[2(2-aminoethoxy)ethoxymethyl]-4-(2,3 -dichlorophenyl)-6 methyl 1,4-dihydropyridine-3,5-dicarboxylate) is a powerful ligand for the visualization of the cardiac calcium channel in vivo using PET. The aim of the present study was to synthesize a li pophilic, nonionized derivative of S11568 to facilitate its penetratio n into the brain. To increase the lipophilicity and to remove simultan eously the ionic nature of our ligand, the N-tert-butoxycarbonyl (N-Bo c) derivative of S11568 was synthesized. An IC50 value of 1.7 nM for t his derivative confirmed that both the affinity and selectivity for th e calcium channel was unaltered by this chemical modification (S11568 with IC50 value of 9.9 nM). The biologically more active enantiomer of S11568, the levogyre isomer S12968, was labelled with C-11 using [C-1 1]iodomethane. The lipophilicity of the N-Boc derivative-was increased by a factor of three to four when compared to the parent compound las determined by the measurement of the octanol/buffer partition coeffic ients). In vivo, this derivative slightly crosses the blood-brain barr ier, as demonstrated by a 4-fold increase (with respect to the parent compound S12968) of the radioactivity in the brain using the C-11-labe lled N-Boc S12968. This uptake remained too low to be suitable for ima ging calcium channels. (C) 1998 Elsevier Science Inc.