Positron emission tomography (PET) is a medical imaging method which measures the distribution and movement of radiotracers labeled with positron emitting isotopes in the living animal and human body. Its use to measure biochemical transformations and the movement of drugs in the body requires the development radiopharmaceuticals labeled with short lived positron emitting isotopes. Among the positron emitting isotopes, carbon-11 is a very attractive isotope for molecular imaging and drug research. However, because of its short half life (t1/2 = 20.4 min), the chemist must produce the isotope and incorporate it into a radiopharmaceutical in less than 60 minutes.
Imatinib (Gleevec) and letrozole, both are manufactured by Novartis Pharmaceuticals, and are FDA approved drugs for chronic myeloid leukemia and breast cancer, respectively. Because imatinib is an inhibitor of bcr-abl tyrosine kinase, we developed a synthesis of carbon-11 imatinib as a potential diagnostic for bcr-abl tyrosine kinase positive chronic myeloid leukemia. On the other hand, letrozole, an aromatase inhibitor, blocks the last step of estrogen bio-synthesis mediated by aromatase. Carbon-11 labeled letrozole was developed to image aromatase. Both [11C]imatinib and [11C]letrozole are also of interest for measuring drug pharmacokinetics.
We synthesized the unlabeled precursor and product of both imatinib and letrozole. [11C]Methyl iodide and [11C]hydrogen cyanide are generated in their own modules, and used in the syntheis of [ N-11C-methyl]imatinib and [11C-cyano]letrozole in around 80% radiochemical yield by methylation and palladium(0)-mediated cyanide coupling, respectively. When [N-11C-methyl]imatinib was evaluated in a healthy female baboon for pharmacokinetic study, increased carbon-11 uptake was observed in gall bladder, liver, kidneys, and bladder which might represent hepatobiliary and urinary excretion. There was minor carbon-11 uptake that was observed in a spinal cord where the malignancy of chronic myeloid leukemia develops. On the other hand, PET images of baboon brain using [11C-cyano]letrozole indicated non-specific binding throughout the brain with no elevated accumulation in the amygdala where aromatase is abundant. These two labeled drugs provide the opportunity to examine the distribution and pharmacokinetics these two drugs in the brain and peripheral organs in humans.
|Advisor:||Fowler, Joanna S.|
|School:||State University of New York at Stony Brook|
|School Location:||United States -- New York|
|Source:||DAI-B 70/05, Dissertation Abstracts International|
|Subjects:||Pharmacology, Organic chemistry, Radiation|
|Keywords:||Carbon-11, Positron emission tomography, Radiopharmaceuticals|
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