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J Nucl Med. 2008; 49 (Supplement 1):285P
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Radiopharmaceutical Chemistry: New Chemistry-Neurosciences

New Chemistry-Neurosciences Posters

Synthesis and PET studies of [11C]letrozole, an aromatase inhibitor drug

Kun-Eek Kil2, Anat Biegon1, Yu-Shin Ding1, Carolin Ehrlich1, Andre Fischer1, Sung Won Kim1, Deborah Pareto1 and Joanna Fowler1

1 Chemistry Department, Brookhaven National Laboratory, Upton, New York; 2 Department of Chemistry, Stony Brook University, Stony Brook, New York

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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





This Article
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Right arrow Email this article to a friend
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Right arrow Alert me to new issues of the journal
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Google Scholar
Right arrow Articles by Kil, K.-E.
Right arrow Articles by Fowler, J.
PubMed
Right arrow Articles by Kil, K.-E.
Right arrow Articles by Fowler, J.