N-SUBSTITUTED ANALOGS OF 2-BETA-CARBOMETHOXY-3-BETA-(4'-IODOPHENYL)TROPANE (BETA-CIT) WITH SELECTIVE AFFINITY TO DOPAMINE OR SEROTONIN TRANSPORTERS IN RAT FOREBRAIN

This report concerns the synthesis and chemical characterization of no vel series of N-substituted 2 beta-carbomethoxy-3 beta-(4'-iodophenyl) tropan (beta-CIT, 2) analogs and their neuropharmacological evaluation for affinity at dopamine (DA(T)), serotonin (5-HTT), and norepinephri ne membrane transporters in rat brain tissue. N-Substituted analogs of beta-CIT with a 2 beta-carbomethoxy ester moiety showed lower DAT aff inity than beta-CIT for the DA(T), and some were more selective for th e 5-HTT over the DA(T). 2 beta-Carbomethoxy(iodophenyl)nortropane anal ogs of beta-CIT with the N-substituents difluoroethyl, mesoxypropyl, i odopropyl, and methylpropionyl all yielded >10-fold lower DA(T) affini ty than beta-CIT itself, whereas the N-(fluoropropyl)-2 beta-isopropyl ester analog (1) of beta-CIT exceeded beta-CIT (2, an N-methyl-2 beta -carbomethoxy ester) in DA(T) affinity. Several N-haloalkyl-substitute d beta-CIT analogs yielded high 5-HTT affinity (K-i < 0.6 nM), ranking : N-fluoropropyl (5) > N-chloropropyl (4) greater than or equal to N-b romopropyl (3) > beta-CIT (2) > N-3'-phthalimidopropyl (11), with part icularly high (ca. 30-fold) 5-HTT-over-DA(T) selectivity found in the N-fluoropropyl (5) and N-fluoroethyl (6) compounds, compared to only 3 .0-fold 5-HTT selectivity in beta-CIT itself. Highly 5-HTT selective a gents such as 5 and 6 may be useful as brain-imaging ligands for serot onin neurons or as mood-elevating drugs, while the high affinity and s electivity for the DA transporter found in N-(fluoropropyl)-2 beta-(ca rboxyisopropyl)-3 beta nortropane (1) and N-(fluoropropyl)-2 beta-carb oxymethoxy-3 beta-(4'-iodophenyl)-nortropane (FP-beta-CIT; 5) support their use as improved markers for DA neurons.