Synthesis and in Vivo Validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin- 1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione: A Novel 5-HT1A Receptor Agonist Positron Emission Tomography Ligand

J Med Chem. 2006 Jan 12;49(1):125-34. doi: 10.1021/jm050725j.


Antagonist 5-HT(1A) PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-(11)C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (10), a potential high affinity (K(i) = 1.36 nM) 5-HT(1A) agonist PET tracer is described. Piperazine 10 is a 5-HT(1A) agonist with an EC(50) comparable to serotonin, based on cAMP formation and GTP(gamma)S binding assays. Radiosynthesis of [(11)C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [(11)C]CH(3)OTf in 25 +/- 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [(11)C]10 were >99% with a specific activity 1500 +/- 300 Ci/mmol (n =15). PET studies in anesthetized baboon demonstrate [(11)C]10 specific binding in brain regions rich in 5-HT(1A) receptors. Binding of [(11)C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V(T)) of [(11)C]10 in baboon correlate with [(11)C]WAY100635 V(T) in baboons. These data provide evidence that [(11)C]10 is the first promising agonist PET tracer for the 5-HT(1A) receptors.

Publication types

  • Research Support, N.I.H., Extramural
  • Validation Study

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • Brain / drug effects
  • CHO Cells
  • Cricetinae
  • Ligands
  • Male
  • Molecular Structure
  • Papio
  • Piperazines / antagonists & inhibitors
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology*
  • Positron-Emission Tomography / methods*
  • Pyridines / pharmacology
  • Serotonin 5-HT1 Receptor Agonists*
  • Time Factors
  • Tissue Distribution
  • Triazines / antagonists & inhibitors
  • Triazines / chemical synthesis*
  • Triazines / pharmacology*


  • 2-(4-(4-(7-methoxynaphthalen-1-yl)piperazin-1-yl)butyl)-4-methyl-2H-(1,2,4)triazine-3,5-dione
  • Ligands
  • Piperazines
  • Pyridines
  • Serotonin 5-HT1 Receptor Agonists
  • Triazines
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • 8-Hydroxy-2-(di-n-propylamino)tetralin