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

J Med Chem. 1996 Jan 19;39(2):543-8. doi: 10.1021/jm9505324.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Carrier Proteins / metabolism*
  • Cocaine / analogs & derivatives*
  • Cocaine / chemistry
  • Cocaine / metabolism
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Magnetic Resonance Spectroscopy
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Molecular Probes
  • Nerve Tissue Proteins*
  • Prosencephalon / metabolism*
  • Radioligand Assay
  • Rats
  • Serotonin / metabolism
  • Serotonin Plasma Membrane Transport Proteins
  • Spectrometry, Mass, Fast Atom Bombardment


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Molecular Probes
  • Nerve Tissue Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a3 protein, rat
  • Slc6a4 protein, rat
  • Serotonin
  • 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
  • Cocaine
  • Dopamine