# Molecular imaging of PS1/gamma-secretase and analysis of Alzheimer's disease.

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $208,640

## Abstract

PROJECT SUMMARY
 Selectively modulating γ-secretase activity has emerged as a therapeutic strategy for Alzheimer's disease
(AD) because it controls the levels of pathogenic Aβ42 species. We have developed a class of γ-secretase
modulators (GSMs), a group of small molecules that specifically modulate γ-secretase processing of APP by
binding γ-secretase's PS1 components and thus preferentially lower Aβ42 levels over Aβ40, while increasing the
levels of shorter Aβ species. Our GSMs do not affect the cleavage of other γ-secretase substrates, e.g. Notch.
Our GSM program evolved several generations of development. Recently, we have developed a novel series
of pyridazine class SGSMs which displayed unprecedented level of efficacy in lowering Aβ42 levels in cell and
animal-based studies, with desirable drug-like properties, thus making them outstanding AD clinical
candidates. We have reported a lead clinical candidate within this new class, SGSM-15606 (IC50 of Aβ42
=7nM). This molecule and related analogs have been developed with a plan for a pre-Investigational New Drug
(IND) inquiry toward an AD intervention trial.
 Our GSM program has provided a unique opportunity to characterize the in vivo selectivity, distribution and
involvement of γ-secretase in the pathophysiology of AD by molecular imaging. Among the non-invasive
imaging techniques, positron emission tomography (PET) is an ideal tool to deliver answers to fundamental
questions about γ-secretase in the living human brain. Furthermore, it provides a method to both investigate γ-
secretase mechanisms non-invasively and improve drug development. During the past decade, there are
several potential disease-modifying therapies for AD advanced to clinical trials. However, the AD therapeutics
have a high failure rate for clinical trials partly due to the heterogeneous nature of enrolled patients. In AD
trials, patients have been typically recruited under broad diagnostic categories, which is usually related to
inconclusive or negative trial outcomes. To address this issue, clinical studies have recently started to apply
PET imaging to choose more homogeneous patient groups. For example, the use of PET ligands for Aβ
plaques and neurofibrillary tau tangles have become more routine in clinical trials and enabling better definition
of optimal patient groups for clinical trials.
 In our proposal, we will develop new GSM-based γ-secretase PET imaging probes to serve as a
translational tool to help clinical characterization of GSMs by measuring in vivo target occupancy. The results
of our studies should facilitate a potential clinical trial of our SGSMs for AD intervention. Additionally, with the
availability of our PET probe, the properties of γ-secretase in AD patients could be quantified for the first time,
which may ultimately provide a more comprehensive understanding of AD etiology.

## Key facts

- **NIH application ID:** 9901420
- **Project number:** 5R21AG062913-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Changning Wang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $208,640
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9901420

## Citation

> US National Institutes of Health, RePORTER application 9901420, Molecular imaging of PS1/gamma-secretase and analysis of Alzheimer's disease. (5R21AG062913-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9901420. Licensed CC0.

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