Specificity of diastereomers of [99mTc]TRODAT-1 as dopamine transporter imaging agents

J Med Chem. 1998 Feb 12;41(4):428-36. doi: 10.1021/jm970742b.


Recently, we reported the first human study of [99mTc]TRODAT-1, technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2- yl]methyl](2-mercaptoethyl)amino]ethyl]amino]-ethanethiolato(3-)-o xo- [1R-(exo-exo)]-, as an imaging agent of central nervous system (CNS) dopamine transporters. Due to the existence of several chiral centers on this molecule, upon the formation of [99mTc]TRODAT-1 complex (2) several diastereomers could be created. Two major diastereomers of [99mTc]TRODAT-1 (2), designated as peak A (2A) and peak B (2B), were separated by HPLC. Biodistribution of the purified diastereomers 2A,B was evaluated in rats. It appears that 2A displayed a higher lipophilicity than 2B (PC = 305 and 229, respectively), and a similar trend was observed for the initial brain uptake at 2 min postinjection (0.50% and 0.28% dose/organ for 2A,B, respectively). At 60 min post-iv-injection, the specific uptakes, as measured by [striatum - cerebellum]/cerebellum ([ST-CB]/CB) ratio, were 1.72 and 2.79 for 2A,B, respectively. The higher [ST-CB]/CB ratio observed for 2B was corroborated by the results of an in vitro binding assay. Higher binding affinity for dopamine transporters was observed for 3B (Ki = 13.87 and 8.42 nM for the analogous rhenium complexes 3A,B, respectively). The structure of the [99mTc]TRODAT-1 complexes was deduced using nonradioactive rhenium as a surrogate for radioactive technetium complex. Reacting free TRODAT-1 ligand with [Bu4N][ReOCl4] yielded two major complexes: Re-TRODAT-1A (3A) and Re-TRODAT-1B (3B) (corresponding with peaks A and B of [99mTc]TRODAT-1, respectively), whose structures were determined by X-ray analysis. The X-ray structures show that both complexes have a pseudo-square-pyramidal structure of [RevO]3+N2S2 core with oxygen occupying the apical position and the N-alkyl substitution in syn-configuration to the oxo-rhenium bond. In conclusion, TRODAT-1 formed at least two diastereomers after complexing with a metal(V)-oxo (M = 99mTc, Re) center core. The two isomers display different binding affinities toward dopamine transporters and distinct properties of localization in the striatum area of the brain where the transporters are located.

Publication types

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

MeSH terms

  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Carrier Proteins / analysis*
  • Carrier Proteins / metabolism
  • Corpus Striatum / diagnostic imaging
  • Corpus Striatum / metabolism
  • Crystallography, X-Ray
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Humans
  • Indicators and Reagents
  • Male
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Models, Molecular
  • Molecular Conformation
  • Nerve Tissue Proteins*
  • Organ Specificity
  • Organotechnetium Compounds / chemical synthesis*
  • Organotechnetium Compounds / pharmacokinetics
  • Papio
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tomography, Emission-Computed, Single-Photon
  • Tropanes / chemical synthesis*
  • Tropanes / pharmacokinetics


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Indicators and Reagents
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Organotechnetium Compounds
  • Radiopharmaceuticals
  • Tropanes
  • technetium Tc 99m TRODAT-1
  • Dopamine