The proposed research involves the development of positron emission tomography (PET) radiopharmaceuticals that localize in the brain of human subjects based upon their selective binding to beta- sheet fibrils found in amyloid-beta (Ap) protein. The deposition of Ap in brain is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Our plan is to rationally design, synthesize, develop, and apply selective and potent A(3-binding fluorine-18-labeled PET radioligands capable of penetrating the blood- brain barrier and selectively binding to Ap deposits in the brains of living human subjects with high affinity. The structure of many of these radioligands is based upon lead compounds related chemically to the well known amyloid-selective dye Thioflavin T. It is anticipated that the application of the proposed 18F-labeled AP radioligands will make possible direct assessment of cerebral Ap burden and response to therapeutic strategies aimed at halting or reversing Ap deposition in the brains of human subjects. The 110 min half-life of the 18F-radionuclide label will make regional distribution of the Ap-specific PET radiopharmaceuticals practical in the same manner as has been realized for F-18-labeled FDG.
Our specific aims i nclude: 1) rationally design, synthesize, and evaluate the in vitro properties of a selected array of Ap-binding agents containing fluorine in a position that can be readily radiolabeled;2) radiolabel the most promising compounds with the high specific activity, positron-emitting radionuclide 18F;3) assess the in vivo properties of these radiotracers in normal control rodents;4) assess the in vivo properties of the 18F-labeled radiotracers in normal control baboons using PET imaging;5) take three 18F- labeled Ap agents into pilot human PET imaging studies in 5 AD and 5 age-matched control subjects to assess their in vivo imaging properties relative to the 11C-labeled AP radiotracer Pittsburgh Compound-B (PIB) in the same subjects;and 6) select one 18F-labeled amyloid agent to perform more extensive human PET imaging studies in 10 control subjects, 10 subjects with mild cognitive impairment (MCI), and 10 AD subjects, and compare its imaging properties to those of PIB.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018402-08
Application #
7795732
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Hsiao, John
Project Start
2000-07-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2013-02-28
Support Year
8
Fiscal Year
2010
Total Cost
$357,159
Indirect Cost
Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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