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

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2021 · $332,333

## 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 familial frontal temporal dementias (fFTDs). Several useful PET agents for imaging mixed 3R+4R-
tau aggregates in Alzheimer's disease (AD) have been reported, although none of these agents has proven
useful for imaging 4R-tau in non-AD 4R-tauopathies. 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 ligands for aggregated 4R-tau,
identifying the most promising leads to advance to in vivo studies in rodents and non-human primates. Initially,
Project 2 will obtain human tissue binding data using two compounds with favorable 4R-tau binding properties,
PM-PBB3 and CBD-2115, and will fully define their binding characteristics in a variety of human post-mortem
tissues. Subsequently, the MCRC will prepare a series of analogs of PM-PBB3 and CBD-2115 for in vitro binding
assays in Project 2 to help define the structure-activity relationship (SAR) of the analogs. The MCRC will employ
its computational chemistry resources to help guide the selection of PM-PBB3 and CBD-2115 analogs for
synthesis and subsequent evaluation and will also generate new lead compounds for testing in Project 2. In vitro
binding assays conducted in Project 2 will test the predictive power of the in silico studies conducted by the
MCRC and help refine binding site features that most influence radioligand-4R-tau interactions. These
refinements will assist future in silico screening studies conducted by the MCRC aimed at providing new 4R-tau
ligands for testing in Project 2. 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 fFTD subjects
in the Clinical Core.

## Key facts

- **NIH application ID:** 10241513
- **Project number:** 5U19NS110456-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** CHESTER A MATHIS
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,333
- **Award type:** 5
- **Project period:** 2019-09-24 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241513

## Citation

> US National Institutes of Health, RePORTER application 10241513, In Vitro and In Vivo Characterization of PET Radiotracers for the 4R Variant of Tau (5U19NS110456-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241513. Licensed CC0.

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