# In Vitro and In Vivo Characterization of PET Radiotracers for the 4R Variant of Tau

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2024 · $372,083

## Abstract

PROJECT 2: Development of 4R-Tau PET Radioligands for Imaging Tauopathies
ABSTRACT
The goal of Project 2 is to develop a positron emission tomography (PET) radiopharmaceutical useful for imaging
4-repeat (4R) tauopathies, which include progressive supranuclear palsy (PSP), corticobasal degeneration
(CBD), and frontotemporal lobar degeneration (FTLD-tau). Several useful PET agents for imaging mixed 3R/4R-
tau aggregates in Alzheimer’s disease (AD) have been reported, but none of these agents has proven highly
sensitive for imaging 4R-tau in non-AD 4R-tauopathies, and higher affinity 4R-tau radioligands are needed to
improve specific binding signal in vivo. Novel disease modifying therapies that target tau offer new treatment
possibilities for patients with different tauopathies. Key to a successful therapeutic strategy will be the ability to
discriminate patients with different tauopathies and to assess the efficacy of anti-tau treatments. The proposed
research in this project will pursue parallel tracks of lead compound identification and optimization, working
closely with the Medicinal Chemistry and Radiochemistry Core (MCRC) to identify new 4R-tau candidate
radioligands for subsequent evaluation in Project 2. Binding studies in tissue specimens of 4R-tauopathies and
other proteinopathies will characterize the sensitivity and specificity of candidate radioligands for binding to
aggregated 4R-tau, identifying the most promising leads to advance into in vivo studies in rodents and non-
human primates. The MCRC will prepare a series of analogs from two lead series: Z-indoles and substituted-
indazoles for in vitro binding assays in Project 2 and further define the structure-activity relationship of the
analogs. The MCRC will employ its computational resources to help guide the selection of new analogs to be
purchased from commercial sources or synthesized by the MCRC, and subsequently evaluated in Project 2. In
vitro binding assays conducted in Project 2 will test the predictive power of the in silico molecular similarity
studies conducted by the MCRC and help refine binding site features that most influence radioligand-4R-tau high
affinity binding interactions. Project 2 will employ a staged approach using both in vitro and in vivo assay
methods to characterize and evaluate candidate 4R-tau PET imaging agents provided by the MCRC, identifying
the most promising 4R-tau agents for subsequent evaluation in first-in-human studies of PSP and FTLD-tau
subjects in the Clinical Core.

## Key facts

- **NIH application ID:** 10940635
- **Project number:** 2U19NS110456-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** CHESTER A MATHIS
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,083
- **Award type:** 2
- **Project period:** 2019-09-24 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940635

## Citation

> US National Institutes of Health, RePORTER application 10940635, In Vitro and In Vivo Characterization of PET Radiotracers for the 4R Variant of Tau (2U19NS110456-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10940635. Licensed CC0.

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