The cholinergic innervation to the neocortex and nucleus basalis from which it is derived both show marked pathological changes in patients with Alzheimer's disease (AD). Although other neurotransmitter-containing long axon projections to the cortex are also affected, recent evidence from biopsy samples suggests that deficiencies in acetylcholine and choline acetyltransferase (CHAT) are two of the earliest neurochemical changes in AD. Progress in the clinical diagnosis of AD has been slowed by the absence of reliable and specific in vivo tests of neurotransmitter and receptor function in patients with dementia. Therefore, development of physiological imaging agents specific for AD may improve clinical diagnosis of AD. This application seeks funds for the development of radiotracers for in vivo imaging of cholinergic pathways with Single Photon Emission Computed Tomography (SPECT). The vesicular ACh transporter has used as targets for the design of these radiotracers. Potent and selective inhibitors of vesicular ACh uptake will be developed based on the lead compound vesamicol. Following their administration to animals, the initial regional cerebral distribution of these radiolabelled agents should reflect patterns of perfusion. Subsequent selective binding to the target (the vesicular ACh transporter) , accompanied by efflux of the tracer from areas of non-specific binding, should highlight regions of cholinergic innervation. In the course of this project, the following studies will be carried out: Synthesis of a number of vesamicol analogs screening of these agents for in vitro vesamicol receptor (VR) binding; Radiolabelling of the compounds and regional tracer measurements in rats; Toxicity measurements (LD50 in mice); Autoradiographic localization in the rat and post-mortem human brain; and in vivo imaging of cholinergic pathways in the Macaque brain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013621-06
Application #
2555138
Study Section
Diagnostic Radiology Study Section (RNM)
Project Start
1992-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1999-06-30
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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