Novel radiotracers for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(phenylthio)araalkylamines

J Med Chem. 2000 Aug 10;43(16):3103-10. doi: 10.1021/jm000079i.

Abstract

A series of four 2-(phenylthio)araalkylamines have been radiolabeled with (11)C and evaluated as potential radiotracers for imaging the serotonin transporter (SERT) by positron emission tomography (PET). All four candidates display high affinity for SERT and low affinity for the dopamine or norepinephrine transporters using in vitro binding assays. Biodistribution studies in rats demonstrated that tail-vein injection of the (11)C-labeled radiotracers resulted in high brain uptake of radioactivity with a preferential distribution in brain regions known to be rich in SERT such as hypothalamus and thalamus. The most promising candidate, 16, had hypothalamus-to-cerebellum ratios of 9:1, 1 h postinjection, an indication of high specific to nonspecific binding. Ex vivo pharmacological studies demonstrated that uptake in SERT-rich brain regions was both saturable and selective for SERT. Two of the tested radiotracers, 15 and 16, have highly favorable properties for imaging SERT and will be used in pilot human PET imaging studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis*
  • Aniline Compounds / chemistry
  • Aniline Compounds / metabolism
  • Animals
  • Brain / metabolism
  • Carbon Radioisotopes
  • Carrier Proteins / metabolism*
  • Humans
  • In Vitro Techniques
  • Isotope Labeling
  • Ligands
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Membranes
  • Nerve Tissue Proteins*
  • Protein Binding
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin / metabolism*
  • Serotonin Agents / toxicity
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship
  • Sulfides / chemical synthesis*
  • Sulfides / chemistry
  • Sulfides / metabolism
  • Tomography, Emission-Computed
  • p-Chloroamphetamine / toxicity

Substances

  • 2-(2-dimethylaminomethylphenylsulfanyl)-5-methoxyphenylamine
  • 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile
  • Aniline Compounds
  • Carbon Radioisotopes
  • Carrier Proteins
  • Ligands
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Radiopharmaceuticals
  • SLC6A4 protein, human
  • Serotonin Agents
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, rat
  • Sulfides
  • Serotonin
  • p-Chloroamphetamine