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 novel series of N-substituted 2 beta-carbomethoxy-3 beta-(4'-iodophenyl)tropane (beta-CIT, 2) analogs and their neuropharmacological evaluation for affinity at dopamine (DAT), serotonin (5-HTT), and norepinephrine membrane transporters in rat brain tissue. N-Substituted analogs of beta-CIT with a 2 beta-carbomethoxy ester moiety showed lower DAT affinity than beta-CIT for the DAT, and some were more selective for the 5-HTT over the DAT. 2 beta-Carbomethoxy(iodophenyl)nortropane analogs of beta-CIT with the N-substituents difluoroethyl, mesoxypropyl, iodopropyl, and methylpropionyl all yielded > 10-fold lower DAT affinity 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 DAT affinity. Several N-haloalkyl-substituted beta-CIT analogs yielded high 5-HTT affinity (Ki < 0.6 nM), ranking: N-fluoropropyl (5) > N-chloropropyl (4) > or = N-bromopropyl (3) > beta-CIT (2) > N-3'-phtalimidopropyl (11), with particularly high (ca. 30-fold) 5-HTT-over-DAT selectivity found in the N-fluoropropyl (5) and N-fluoroethyl (6) compounds, compared to only 3.o-fold 5-HTT selectivity in beta-CIT itself. Highly 5-HTT selective agents such as 5 and 6 may be useful as brain-imaging ligands for serotonin neurons or as mood-elevating drugs, while the high affinity and selectivity for the DA transporter found in N-(fluoropropyl)-2 beta-(carboxyisopropyl)-3 beta-(4'-iodophenyl)-nortropane (1) and N-(fluoropropyl)-2 beta-carboxymethoxy-3 bet-(4'-iodophenyl)nortropane (FP-beta-CIT, 5) support their use as improved markers for DA neurons.
Neumeyer
J L
JL
Research Biochemicals International (RBI), Natick, Massachusetts 01760, USA.
Tamagnan
G
G
Wang
S
S
Gao
Y
Y
Milius
R A
RA
Kula
N S
NS
Baldessarini
R J
RJ
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D009682:Magnetic Resonance Spectroscopy; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D016548:Prosencephalon / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D016339:Spectrometry, Mass, Fast Atom Bombardment
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D012701:Serotonin; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine; D004298:Dopamine