Improving imaging tools for diagnosis of AD

Vijay Sharma, PhD
Washington University (St. Louis, MO)
Year Awarded:
2007
Grant Duration:
April 1, 2007 to September 30, 2010
Disease:
Alzheimer's Disease
Award Amount:
$150,000
Grant Reference ID:
A2007383
Award Type:
Pilot
Award Region:
US Midwestern

Imaging PGP-Mediated Transport in Alzheimer's Disease

Summary

We propose to evaluate the potential of lead Pgp-targeted agent to act as noninvasive probe to detect those defects in brains of mouse models via PET imaging. Additionally, our strategy is amenable to kit formulation with potential for widespread deployment of a test for managing AD.

Details

Alzheimer's Disease (AD) patients demonstrate loss of neurons in regions of the brain responsible for learning and memory (hippocampus) and the presence of distinct protein aggregates, commonly known as amyloid plaques. Emerging new models for occurrence of the disease indicate that pathways in disease progression are likely mediated by transporters prevalent in the brain. Among these transporters, P-glycoprotein (Pgp) known to block penetration of numerous drugs or cytotoxins into brain may likely be involved in buildup of amyloid plaques within the brains of AD patients. We hypothesize that natural function involving Pgp mediating efflux of amyloid plaques out of the CNS may likely be compromised in diseased patients compared with the normal ones and the process initiates prior to appearance of symptoms for the disease. Thus, ultrasensitive-diagnostic agents capable of evaluating that novel risk factor in terms of individual variations in Pgp transport would likely assist in patient stratification and guide therapeutic choices. Herein, we propose to evaluate the potential of lead Pgp-targeted agent to act as noninvasive probe to detect those defects in brains of mouse models via PET imaging. Additionally, our strategy is amenable to kit formulation with potential for widespread deployment of a test for managing AD.

Publications

Sivapackiam, J., Gammon, ST, Harpstrite, SE, Sharma, V. (2010) Targeted chemotherapy in drug-resistant tumors, noninvasive imaging of P-glycoprotein-mediated functional transport in cancer, and emerging role of Pgp in neurodegenerative diseases. Methods Mol Biol. 596:141-181  

Sivapackiam J, Harpstrite SE, Prior JL, Gu H, Rath NP, Sharma V. (2010) Synthesis, molecular structure, and validation of metalloprobes for assessment of MDR1 P-glycoprotein-mediated functional transport. Dalton Transactions 39(25):5842-50  

Sivapackiam, J, Harpstrite, SE, Prior, J, Piwnica-Worms, D, Sharma, V. SPECT Metalloprobes for monitoring MDR1 P-glycoprotein-mediated functional transport at the blood-brain barrier (BBB) Submitted to TETRACHEM Proccedings 2010 [PMID:nd][link not available]
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