Vesicular acetylcholine transporter (VAChT) is a reliable biomarker for studying the loss of cholinergic neurons and synapses. Cholinergic deficits are associated with impairment in memory, motor function and cognitive functions. A PET tracer for clinical imaging of VAChT will provide a critical noninvasive tool to measure cholinergic deficits and assess disease severity of patients with Alzheimer disease, Parkinson disease, progressive supranuclear palsy (PSP) and other dementias. It can also be used to monitor the efficacy of cholinergic therapies in neurological diseases. Under our previously funded R01 for the discovery of PET imaging agents for imaging the VAChT, we developed [18F]VAT and [11C]TZ659. Both have high potency (Ki ? 1.0 nM) and selectivity for VAChT versus sigma receptors (>1000-fold) and showed promise in rodent and nonhuman primate studies. More importantly, by the end of the five year funding period, we completed imaging dosimetry studies in nonhuman primates, rodent toxicity studies, and the SOP for automated production of [18F]VAT in our cGMP facilities. Approval of our eIND, IRB and RDRC applications for [18F]VAT enabled a pilot PET imaging in eight healthy human subjects that demonstrated: (a) high reproducibility and reliability of [18F]VAT production in the cGMP facility; (b) no observable adverse effects in research subjects; (c) high specificity for the VAChT-enriched striatal region with target: non-target ratio of 6.0; and (d) favorable kinetic with high striatal accumulation 20 min post-injection, and rapid washout from non-target cerebellar hemispheres. Therefore, the goal of this R01 renewal is to focus on translational studies of [18F]VAT in healthy control subjects to provide key measures of radiation dosimetry, variability within and between subjects, age-dependence and sex-dependence. These validation studies will provide the basis for future investigations of pathologic conditions. In addition, we will use nonhuman primates pre-treated with a D2 dopamine receptor agonist or antagonist to investigate their impact on brain VAChT expression assessed by PET with [18F]VAT. Finally, we will determine the feasibility of quantitatively imaging VAChT in patients with PSP-RS and compare the in vivo PET findings to in vitro autoradiography studies using [3H]VAT for postmortem brain tissues from cases with autopsy proven PSP.

Public Health Relevance

The loss of cholinergic neurons contribute cognitive impairment of patients with dementia including Alzheimer disease (AD) Parkinson disease (PD), and progressive supranuclear palsy (PSP). PSP appears in mid- to late adulthood, most patients are identified in their 60s. Patients with PSP usually survive 5 to 9 years after the disease first appears. About 20,000 people in USA have PSP and no effective treatment available. An F-18 labeled clinical suitable PET agent targeting vesicular acetylcholine transporter, would be a valuable clinical tool for noninvasive monitoring cholinergic dysfunction in patients with PSP and other dementias. It will be a novel methodology for evaluating the therapeutic efficacy of treating neurological diseases using cholinergic inhibition strategy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075527-08
Application #
9697647
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Babcock, Debra J
Project Start
2011-06-15
Project End
2022-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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