# Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $814,874

## Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder afflicting 6 million Americans. The
clinical dementia of AD is coupled to a distinct pathology, with -amyloid plaques, neurofibrillary tangles, and
synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major
structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is
detectable in individuals with the prodromal stage of mild cognitive impairment (MCI).
 Positron Emission Tomography (PET) imaging is increasingly employed in the study of AD. However, until
recently there have been no PET radiotracers that can directly image synaptic density in vivo, which would be
of high value in AD diagnosis, as well as in monitoring efficacy of treatments. We have developed 11C-UCB-J
as a radiotracer for PET imaging and quantification of the synaptic vesicle glycoprotein-2A (SV2A). In studies
in healthy human subjects, 11C-UCB-J displayed excellent properties for quantitative PET imaging of SV2A in
the human brain. We have also validated SV2A as an in vivo biomarker for synaptic density. Initial imaging
results in MCI/AD patients show specific and distinct SV2A reductions, most pronounced (30-40%) in the
hippocampus, which is expected and consistent with postmortem studies, where early degeneration of the
entorhinal cortical cell projection to hippocampus and hippocampal SV2A reductions have been observed.
Thus, based on these data, 11C-UCB-J appears to be an excellent radiotracer for quantitative imaging of SV2A
in the human brain and 11C-UCB-J PET can be an extremely useful in vivo biomarker of synaptic loss in AD.
 Although 11C-UCB-J proves to be an excellent tracer for synaptic density imaging, a significant drawback is
the short half-life (t1/2 = 20.4 min) of its 11C-radiolabel, which precludes its central production and distribution to
multiple sites for imaging use, and thus limits its wide application in multi-center clinical trials or as diagnostic
agent in clinics. For AD in particular, where drug clinical trials at many institutions are ongoing, the need for a
longer-lived radiotracer is evident and one labeled with the 18F-radioisotope (t1/2 = 109.8 min) will be
appropriate. Analogous to the development of 11C-PIB and its FDA-approved 18F-labeled counterpart 18F-
flutemetamol (Vizamyl®) for -amyloid imaging in AD, in this application we propose to develop18F-SDM-8, the
difluorinated analog of UCB-J, for human neuroimaging, and to validate its use as a imaging biomarker of
synaptic loss in MCI/AD. The goal is to provide a “neuroimaging biomarker of synaptic density” for use in
the study of the AD continuum and potential diagnosis of AD in its earliest, prodromal stage, as well as in the
monitoring of disease progression and efficacy of emerging AD therapies. In addition to AD, the availability of
18F-SDM-8 PET as a general imaging biomarker of synaptic density will enable the investigat...

## Key facts

- **NIH application ID:** 9865068
- **Project number:** 1R01AG065474-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YIYUN HENRY HUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $814,874
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9865068

## Citation

> US National Institutes of Health, RePORTER application 9865068, Validation of Fluorine-18 radioligand for PET imaging of synaptic density in Alzheimer's disease (1R01AG065474-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9865068. Licensed CC0.

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