Aromatase, the cyp19A gene product, is the enzyme responsible for estrogen synthesis. To date, there are no quantitative studies of the distribution and regulation of aromatase in living humans. Using a newly developed method of synthesis and purification, we propose to 1. Validate and characterize [11C]vorozole as a PET radiotracer for the non invasive assessment of aromatase in the brain and peripheral organs of living humans:
This aim will address the human dosimetry, pharmacological specificity and kinetic modeling of the radiopharmaceutical. 2. Examine the effects of age, sex and gonadal hormones on the kinetic parameters of [11C]vorozole. For this aim, PET studies will be performed in men and women, young and old, and young women will be studied at different phases of the menstrual cycle. Gonadal hormone plasma levels will be assayed in all subjects. 3. Examine the effects of cigarette smoking on aromatase availability in the brain and peripheral organs. Both smokers and non-smokers will be recruited to address this aim. The data gathered from these studies will serve as the basis for an IND application, opening the way for studies using aromatase as a biomarker for drug discovery and for pathophysiological studies of CNS disorders in various pathologies. Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer's disease, endometriosis, liver cancer, ovarian cancer and brain injury;which affect millions in the US. The availability of a validated tracer which can be used to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors (AI) in different diseases, facilitate AI treatment monitoring and provide a tool for new AI drug development and evaluation.

Public Health Relevance

Changes in aromatase activity are implicated in a wide range of human diseases, including breast cancer, Alzheimer's disease, endometriosis, liver cancer and brain injury;which affect millions in the US and have a major impact on public health. The ability to use [11C]vorozole to detect changes in aromatase non-invasively will have a dramatic impact on the ability to select patients who can benefit from aromatase inhibitors, facilitate aromatase inhibitor treatment monitoring and provide a new tool for the development and evaluation of new aromatase inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB012707-02
Application #
8217150
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Christina
Project Start
2011-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$220,490
Indirect Cost
$120,490
Name
Brookhaven National Laboratory
Department
Type
DUNS #
027579460
City
Upton
State
NY
Country
United States
Zip Code
11973
Logan, Jean; Kim, Sung Won; Pareto, Deborah et al. (2014) Kinetic analysis of [11C]vorozole binding in the human brain with positron emission tomography. Mol Imaging 13:1-12