IN-VITRO AND IN-VIVO CHARACTERIZATION OF NEWLY DEVELOPED IODINATED 1-(2-[BIS(4-FLUOROPHENYL)METHOXY]ETHYL) PIPERAZINE DERIVATIVES IN RATS -LIMITED VALUE AS DOPAMINE TRANSPORTER SPECT LIGANDS

A series of 1-{2-[bis(4-fluorophenyl)methoxy]ethyl}piperazines (CYD1, 2, 3, 5) with a 4-substituent incorporating a 1-hydroxy-3-iodo-2-prope nyl moiety, except CYD2 which lacks the hydroxy, was synthesized as po tential in vivo imaging ligands for the dopamine transporter. For two of the piperazine derivatives (CYD3 and 5), possible stereoselectivity was considered as well (both E- and Z-form). Their in vitro potency f or inhibition of [H-3]dopamine uptake in rat striatal synaptosomes was 10-fold lower than that of GBR 12909 used as a reference. The highest K-i values were 137 and 101 nM for CYD1E and CYD3E, respectively. Inh ibition potency was higher for the E- than for the Z-isomers. In vivo distribution of radioactivity in rats injected with the I-123-labeled CYDs showed preferred striatal uptake for CYD1E and CYD3E as compared to the cerebellum and occipital cortex. Although the E-isomer of CYD3 showed the best in vitro and in vivo binding characteristics, its stri atal uptake ratios (maximal value: 2.7 for striatum-to-cerebellum at 4 h p.i.) are too low to consider application in human Single Photon Em ission Computed Tomography studies. (C) 1996 Wiley-Liss, Inc.