Reinvestigation of the synthesis and evaluation of [N-methyl-(11)C]vorozole, a radiotracer targeting cytochrome P450 aromatase

Nucl Med Biol. 2009 Apr;36(3):323-34. doi: 10.1016/j.nucmedbio.2008.12.013.


Introduction: We reinvestigated the synthesis of [N-methyl-(11)C]vorozole, a radiotracer for aromatase, and discovered the presence of an N-methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [N-methyl-(11)C]vorozole.

Methods: Norvorozole was alkylated with [(11)C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ((13)C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-(11)C]vorozole and the contaminating isomer were compared by PET imaging in the baboon.

Results: Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [N-methyl-(11)C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-(11)C]vorozole binds to aromatase. [N-methyl-(11)C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions.

Conclusions: The discovery of a contaminating labeled isomer and the development of a method for isolating pure [N-methyl-(11)C]vorozole combine to provide a new scientific tool for PET studies of the biology of aromatase and for drug research and development.

Publication types

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

MeSH terms

  • Alkylation
  • Animals
  • Aromatase / analysis
  • Aromatase / metabolism*
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Chromatography, High Pressure Liquid
  • Female
  • Hydrocarbons, Iodinated / chemistry
  • Magnetic Resonance Spectroscopy
  • Papio
  • Positron-Emission Tomography
  • Radioactive Tracers
  • Stereoisomerism
  • Time Factors
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / metabolism*


  • Hydrocarbons, Iodinated
  • Radioactive Tracers
  • Triazoles
  • vorozole
  • methyl iodide
  • Aromatase