Abstract
1219
Objectives: The potent aromatase inhibitor, letrozole (4,4’-(1H-1,2,4-triazol-1-ylmethylene)dibenzonitrile, Femara®), is in clinical use in breast cancer and female infertility, and is also used by body builders. Here we synthesized [11C]letrozole for measurement of its pharmacokinetics and for evaluation as a radiotracer for brain aromatase.
Methods: We synthesized letrozole and its bromo-precursor from p-tolunitrile and 4-bromobenzyl bromide respectively in two steps. Letrozole was labeled by aromatic nucleophilic substitution with [11C]cyanide in DMSO catalyzed by tetrakis(triphenylphosphine)palladium(0). [11C]Letrozole pharmacokinetics, reproducibility and specificity were evaluated over a 90 min period in baboon brain with PET.
Results: The nucleophilic aromatic substitution reaction with [11C]cyanide gave [11C]letrozole in >80% RCY and >98% purity and 4.16±2.21 Ci/µmol specific activity. Total synthesis time was 60 min. Its logD and PPB were 1.84 and 48.9% respectively. The labeling reaction was sensitive to solvent and catalyst. PET studies showed rapid uptake followed by a rapid clearance from all brain regions. Pretreatment with 0.1 mg/kg of letrozole showed no blockade.
Conclusions: Nucleophilic [11C]cyanation produced [11C]letrozole in high RCY and purity after optimization of solvent and catalyst. Rapid brain clearance and lack of specific binding indicates that [11C]letrozole is not a useful radiotracer for brain aromatase activity. However, since letrozole is in clinical use and is used recreationally, [11C]letrozole may be useful for pharmacokinetics of the drug in the breast and other target organs in the body.
Research Support: DOE-OBER and NIH/NIDA
- Society of Nuclear Medicine, Inc.