We propose to develop F-18 labeled agents targeting _-amyloid (A_) aggregates for positron emission tomography (PET) imaging of patients with Alzheimer's disease (AD). AD is a common neurodegenerative disease of the brain with a high prevalence in the older population. It is believed that AD is associated with the overproduction and buildup of soluble A_ peptides and insoluble A_ aggregates in the brain. The accumulation of A_ plaques in the brain is thought to be a key risk factor for the pathogenesis of this disease. Currently, there is no imaging method to diagnose AD. Only postmortem biopsy and color staining of the brain tissues for A_ aggregates in senile plaques can definitively diagnose the disease. Therefore, it is extremely important to develop in vivo PET imaging agents for A_ plaques which can be used as biomarkers in the diagnosis and treatment of AD. In the past funding period, we have developed several potent F-18 labeled stilbene derivatives, which show desirable in vitro and in vivo properties as PET imaging agents. In the next funding period, we propose to test additional F-18 labeled biphenyl acetylene and phenyl-naphthalene derivatives. These proposed new agents may have enhanced in vitro and in vivo stability and higher brain uptake as well as better selective localization of A_ plaques in the brain. To accomplish these objectives we will: 1. synthesize the proposed new ligands 2. perform in vitro binding studies using AD brain homogenates to select ligands with good binding affinity (Ki <10 nM). 3. perform 18F labeling studies and test the in vitro stability. 4. study the biodistribution in normal mice (brain uptake >4 %dose/g, at 2 minutes after an iv injection). 5. perform in vitro autoradiography studies using postmortem AD brain sections (to show high and selective A_ plaque-labeling). Ultimately, preferred candidates will be tested in normal non-human primates by positron emission computed tomography (PET) imaging. From this series of novel 18F labeled compounds targeting A_ plaques, one or two final candidates will be selected as PET imaging agents for testing in humans, through which the A_ burden relating to pathological states of AD may be measured. The PET imaging of A_ plaques may be critically useful for the early detection of senile plaques in patients with AD and the monitoring of patients undergoing drug treatment designed to reverse the buildup of A_ plaques in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG022559-07
Application #
8032456
Study Section
Special Emphasis Panel (ZRG1-MEDI-A (09))
Program Officer
Hsiao, John
Project Start
2003-07-01
Project End
2013-02-28
Budget Start
2011-03-01
Budget End
2013-02-28
Support Year
7
Fiscal Year
2011
Total Cost
$307,244
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wu, Zehui; Zha, Zhihao; Li, Genxun et al. (2014) [(18)F](2S,4S)-4-(3-Fluoropropyl)glutamine as a tumor imaging agent. Mol Pharm 11:3852-66
Zhu, Lin; Ploessl, Karl; Kung, Hank F (2014) PET/SPECT imaging agents for neurodegenerative diseases. Chem Soc Rev 43:6683-91
Choi, Seok Rye; Schneider, Julie A; Bennett, David A et al. (2012) Correlation of amyloid PET ligand florbetapir F 18 binding with Aýý aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis Assoc Disord 26:8-16
Zha, Zhihao; Choi, Seok Rye; Ploessl, Karl et al. (2011) Multidentate (18)F-polypegylated styrylpyridines as imaging agents for Aýý plaques in cerebral amyloid angiopathy (CAA). J Med Chem 54:8085-98
Wang, Limin; Qu, Wenchao; Lieberman, Brian P et al. (2011) Synthesis, uptake mechanism characterization and biological evaluation of (18)F labeled fluoroalkyl phenylalanine analogs as potential PET imaging agents. Nucl Med Biol 38:53-62
Carberry, Patrick; Carpenter, Alan P; Kung, Hank F (2011) Fluoride-18 radiolabeling of peptides bearing an aminooxy functional group to a prosthetic ligand via an oxime bond. Bioorg Med Chem Lett 21:6992-5
Carberry, Patrick; Lieberman, Brian P; Ploessl, Karl et al. (2011) New F-18 prosthetic group via oxime coupling. Bioconjug Chem 22:642-53
Zha, Zhihao; Zhu, Lin; Liu, Yajing et al. (2011) Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging. Nucl Med Biol 38:501-8
Kung, Hank F; Choi, Seok Rye; Qu, Wenchao et al. (2010) 18F stilbenes and styrylpyridines for PET imaging of A beta plaques in Alzheimer's disease: a miniperspective. J Med Chem 53:933-41
Liu, Yajing; Zhu, Lin; Plossl, Karl et al. (2010) Optimization of automated radiosynthesis of [18F]AV-45: a new PET imaging agent for Alzheimer's disease. Nucl Med Biol 37:917-25

Showing the most recent 10 out of 22 publications