Pharmacokinetics and brain distribution in non human primate of R(-)[123I]DOI, A 5HT(2A/2C) serotonin agonist

Nucl Med Biol. 2002 Jul;29(5):575-83. doi: 10.1016/s0969-8051(02)00306-2.


Our goal was to synthesize with high specific activity R(-)-1-(2,5-Dimethoxy-4-[123I]iodophenyl)-2-aminopropane [R(-)[123I]DOI], an in vitro potent and selective 5-HT(2A/2C) serotonin agonist, and study in vivo its plasma pharmacokinetics and brain distribution in baboon by SPECT. The purpose was to evaluate this radiotracer as a potential tool in discerning the role of the agonist high affinity state of 5-HT(2) receptors in depression and other neurological disorders. The radiotracer was prepared by electrophilic radioiodination of the N-trifluoroacetyl precursor of R(-)-1-(2,5-Dimethoxyphenyl)-2-aminopropane [R(-)DMA-TFA] with high-purity sodium [123I]iodide in the presence of chloramine-T, followed by amino deprotection with KOH in isopropanol (labeling yield: 73%, radiochemical yield: 62%, radiochemical purity: 99%). In vivo studies in baboon showed high accumulation of radioactivity in thalamus, the frontoparietal cortex, temporal, occipital and the striatum regions, with slightly lower accumulation in the midbrain and cerebellum. Ketanserin did not displaced the radioactivity in any of these brain regions. Plasma metabolite analysis was performed using methanol protein precipitation, the methanol fractions contained from 68% to 92% of the mixture of a labeled metabolite and parent compound. The recovery coefficient of unmetabolized R(-)[123I]DOI was 68%. The percent parent compound present in the extracted fraction, measured by HPLC, decreased gradually with time from 99.8% to 0.3% still present after 4.7 hours post injection whereas the percentage of the only one detected metabolite increased conversely. Free fraction determination (f(1)), was 31 +/- 0.9% (n = 3). For comparison purposes, ex-vivo brain distribution, displacement and metabolite analysis was also carried out in rodents. Although R(-)[123I]DOI displayed good brain uptake and localized in serotonergic areas of the brain, its target to non target ratio and its insensitivity to ketanserin displacement suggest high nonspecific uptake, therefore non potentially useful as brain imaging radiotracer for visualization of the agonist high-affinity state of 5-HT(2A) receptors and for visualizing 5-HT(2C) receptors by SPECT.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamines / chemical synthesis
  • Amphetamines / pharmacokinetics*
  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • Iodine Radioisotopes / chemistry
  • Iodine Radioisotopes / metabolism*
  • Male
  • Papio
  • Radioligand Assay / methods*
  • Radiopharmaceuticals / chemical synthesis
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin
  • Serotonin Receptor Agonists / pharmacokinetics*
  • Tissue Distribution
  • Tomography, Emission-Computed, Single-Photon


  • Amphetamines
  • Iodine Radioisotopes
  • Radiopharmaceuticals
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • 4-iodo-2,5-dimethoxyphenylisopropylamine