# Development of Novel SV2A PET Agents for Early Detection of Alzheimers Disease

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $811,697

## Abstract

ABSTRACT
 The objective of this project is to develop, validate, and translate novel 18F-labeled PET (positron emission
tomography) imaging ligands for synaptic vesicle glycoprotein 2A (SV2A). Such imaging probes are potentially
useful for the early detection of Alzheimer’s disease (AD) through reliable in vivo quantification of synaptic
density. AD is the most common neurodegenerative disease affecting more than 5 million Americans. AD
patients lose their memory and cognitive capacity progressively along a continuum of preclinical stage,
prodromal mild cognitive impairment (MCI), and AD dementia. Although the exact pathogenesis of AD is yet to
be fully understood, and there is currently no cure for the disease, early detection of AD for better intervention
outcomes has become a consensus in AD research community. While the imaging of pathological biomarkers,
such as amyloid-β plaques and hyperphosphorylated tau tangles, have been extensively studied to detect
prodromal AD, the most consistent biomarker of early AD, regional synaptic loss, has been less studied due to
the lack of a suitable PET imaging probe. Because the extent of synaptic loss is a stronger correlate of cognitive
decline than plaques, tangles, and neuronal loss, synaptic density imaging will allow longitudinal assessment of
AD progression, and open a window for early intervention before the onset of devastating symptoms. Through
our pilot PET imaging study using our lead SV2A ligand, 11C-UCB-J, we found significant synaptic loss in the
hippocampus and frontal cortex of patients with MCI and AD. This decrease is more severe in AD (60%
decrease) than MCI (30% decrease), indicating progressive synaptic loss along the disease progression
pathway, which is consistent with findings in postmortem studies. These preliminary data demonstrate the
feasibility and clinical potential of detecting preclinical and prodromal AD by SV2A PET imaging. Therefore, we
propose to develop and translate an 18F-labeled SV2A PET imaging probe for multicenter clinical trials. The
specific aims are: 1) To synthesize a library of SV2A-binding ligands containing fluorine at a position that can be
readily radiolabeled, and evaluate their in vitro binding properties; 2) To radiofluorinate 3-5 of the most promising
ligands for PET imaging evaluation of their in vivo properties, and to select the best ligand for translation to
humans; 3) To correlate SV2A expression with the number of synapses using postmortem brain tissue of patients
with MCI/AD and cognitively intact controls. Successful completion of this project will yield a PET tracer ready to
be tested in multicenter clinical trials as a specific, sensitive, reliable, and quantitative biomarker for early
detection of AD. Early detection of AD by SV2A PET will allow early interventions to slow or halt disease
progression. It will also allow the non-invasive longitudinal tracking of AD progression and objective assessment
of therapeutic effects in clinical tr...

## Key facts

- **NIH application ID:** 9846182
- **Project number:** 5R01AG058773-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Zhengxin Cai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $811,697
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846182

## Citation

> US National Institutes of Health, RePORTER application 9846182, Development of Novel SV2A PET Agents for Early Detection of Alzheimers Disease (5R01AG058773-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9846182. Licensed CC0.

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