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. ? ? ?

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Mathis, Chester A; Kuller, Lewis H; Klunk, William E et al. (2013) In vivo assessment of amyloid-? deposition in nondemented very elderly subjects. Ann Neurol 73:751-61
D'Angelo, Gina M; Weissfeld, Lisa A (2013) Application of copulas to improve covariance estimation for partial least squares. Stat Med 32:685-96
Swaminathan, Shanker; Shen, Li; Risacher, Shannon L et al. (2012) Amyloid pathway-based candidate gene analysis of [(11)C]PiB-PET in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Brain Imaging Behav 6:1-15
Price, Julie C (2012) Molecular brain imaging in the multimodality era. J Cereb Blood Flow Metab 32:1377-92
Mathis, Chester A; Mason, N Scott; Lopresti, Brian J et al. (2012) Development of positron emission tomography ?-amyloid plaque imaging agents. Semin Nucl Med 42:423-32
Cohen, Ann D; Rabinovici, Gil D; Mathis, Chester A et al. (2012) Using Pittsburgh Compound B for in vivo PET imaging of fibrillar amyloid-beta. Adv Pharmacol 64:27-81
Rosario, Bedda L; Weissfeld, Lisa A; Laymon, Charles M et al. (2011) Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET. Neuroimage 55:933-41
Grimmer, Timo; Tholen, Susanne; Yousefi, Behrooz H et al. (2010) Progression of cerebral amyloid load is associated with the apolipoprotein E ?4 genotype in Alzheimer's disease. Biol Psychiatry 68:879-84
Jagust, W J; Landau, S M; Shaw, L M et al. (2009) Relationships between biomarkers in aging and dementia. Neurology 73:1193-9
Lin, Kuo-Shyan; Debnath, Manik L; Mathis, Chester A et al. (2009) Synthesis and beta-amyloid binding properties of rhenium 2-phenylbenzothiazoles. Bioorg Med Chem Lett 19:2258-62

Showing the most recent 10 out of 40 publications