Synthesis and PET studies of [11C-cyano]letrozole (Femara), an aromatase inhibitor drug
Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone to estrone and estradiol respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole, Femara{reg_sign}) is a high affinity aromatase inhibitor (K{sub i}=11.5 nM) which has FDA 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. Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile, 3) were prepared in two-step syntheses from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [{sup 11}C]cyano group was introduced via the tetrakis(triphenylphosphine)palladium(0) catalyzed coupling of [{sup 11}C]cyanide with the bromo-precursor (3). PET studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. The free fraction of letrozole in the plasma, log D, and the [{sup 11}C-cyano]letrozole fraction in the arterial plasma were also measured. [{sup 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/{micro}mol 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. The brain kinetics was not affected by co-injection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9% and log D was 1.84. [{sup 11}C-cyano]Letrozole is readily synthesized via a palladium catalyzed coupling reaction with [{sup 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 brain and peripheral organs.
- Research Organization:
- Brookhaven National Lab. (BNL), Upton, NY (United States)
- Sponsoring Organization:
- USDOE SC OFFICE OF BIOLOGICAL & ENVIRONMENTAL RESEARCH
- DOE Contract Number:
- DE-AC02-98CH10886
- OSTI ID:
- 1044024
- Report Number(s):
- BNL-97208-2012-JA; NMBIEO; R&D Project: MO-085; KP1602010; TRN: US1203317
- Journal Information:
- Nuclear Medicine and Biology, Vol. 36, Issue 2; ISSN 0969-8051
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY
AFFINITY
ANDROGENS
ANDROSTENEDIONE
BABOONS
BRAIN
BROMIDES
CARBON 11
CLEARANCE
CYTOCHROMES
ESTRADIOL
ESTRONE
KINETICS
MAMMARY GLANDS
NEOPLASMS
ORGANS
PALLADIUM
PLASMA
PRECURSOR
SYNTHESIS
TESTOSTERONE
Femara
[11C-cyano] letrozole
positron emission tomography (PET)
aromatase
breast cancer treatment