title: Synthesis and PET studies of [(11)C-cyano]letrozole (Femara), an aromatase inhibitor drug.
abstract: BACKGROUND
  Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (K(i)=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon.
  
  
  METHODS
  Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [(11)C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [(11)C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [(11)C-cyano]letrozole fraction in arterial plasma were also measured.
  
  
  RESULTS
  [(11)C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16+/-2.21 Ci/mumol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84.
  
  
  CONCLUSIONS
  [(11)C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [(11)C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity and saturability in brain regions such as amygdala, which are known to contain aromatase, it may be useful in measuring letrozole distribution and pharmacokinetics in the brain and peripheral organs.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
authors.forename: Kun-Eek
authors.initials: KE
authors.lastname: Kil
authors.forename: Anat
authors.initials: A
authors.lastname: Biegon
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: Andre
authors.initials: A
authors.lastname: Fischer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ferrieri
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Deborah
authors.initials: D
authors.lastname: Pareto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schueller
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
mesh_terms: D000818:Animals; D001141:Aromatase / Q000032:analysis*; D047072:Aromatase Inhibitors; D001921:Brain / Q000201:enzymology*; D002250:Carbon Radioisotopes; D005260:Female; D007553:Isotope Labeling / Q000379:methods*; D000077289:Letrozole; D009570:Nitriles / Q000737:chemistry; D010215:Papio; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D014230:Triazoles / Q000737:chemistry
chemical_list: D047072:Aromatase Inhibitors; D002250:Carbon Radioisotopes; D009570:Nitriles; D019275:Radiopharmaceuticals; D014230:Triazoles; D000077289:Letrozole; D001141:Aromatase