# Medicinal Chemistry and Radiochemistry Core

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2024 · $1,916,146

## Abstract

MEDICINAL CHEMISTRY AND RADIOCHEMISTRY CORE
ABSTRACT
The Medicinal Chemistry and Radiochemistry (MCRC) Core is responsible for the development of radiotracers
for Projects 1 and 2 and the Clinical Core. The MCRC Core is composed of three sites: University of
Pennsylvania (Penn), Washington University in St. Louis (WUSTL), and the University of Pittsburgh (Pitt). The
MCRC also benefits from a collaboration on structural biology through the NINDS U01/U19 Proteinopathy
consortium. The studies conducted during our first 4 years of U19 support have provided 18 putative alpha-
synuclein (Asyn) PET tracers and >10 putative 4R tau radiotracers. We will optimize candidate ligands to
develop: 1) disease-specific radiotracers for imaging Asyn in Parkinson’s disease (PD) or Multiple System
Atrophy (MSA), 2) pan-Asyn radiotracers for both PD and MSA, and 3) 4R tau selective radiotracers for
Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), and frontotemporal dementia (FTD).
The MCRC Core will guide these efforts with a unique combination of 1) chemical biology approaches (photo-
crosslinking MS proteomics and fluorescent probes); 2) structural biology approaches (both solid state NMR and
cryo-electron microscopy); 3) computational modeling (ultra-high throughput screening, molecular dynamics,
and machine learning); and 4) extensive radiochemistry expertise. Chemical biology studies will take place at
Penn in conjunction with structural biology studies done through the U01/U19 Proteinopathy consortium to
determine high resolution structures of the candidate molecules bound to Asyn or tau fibrils, as well as the
selectivity determinants between binding sites. The resulting structural information will be used in computational
modeling and ultra-high throughput screening at Penn to guide the design of new leads. The Asyn compound
synthesis will take place at Penn and WUSTL. The tau lead compound synthesis will take place at Pitt in
collaboration with Penn. These leads will be tested in radioligand competition binding assays, and where
desirable, new radioligands will be synthesized for binding assays and animal experiments. The radiochemistry
studies will be done at Penn to support the rodent imaging studies in Project 1, WUSTL to support the radioligand
binding assays and nonhuman primate imaging studies in Project 1, and Pitt to support the radioligand binding
and non-human primate imaging studies conducted in Project 2. The chemical biology studies of the MCRC
Core, in combination with the structural biology done in collaboration with the U01/U19 Consortium, represents
a comprehensive approach for determining the molecular interactions of U19 radiotracers with Asyn and 4R tau
fibrils isolated from patient brain samples. This structural information will guide the in silico and SAR studies to
generate a suite of high affinity radiotracers that are specific for the different subtypes of the synucleinopathies
(PD and MSA) and 4R tauopathies (C...

## Key facts

- **NIH application ID:** 10940632
- **Project number:** 2U19NS110456-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ROBERT H MACH
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,916,146
- **Award type:** 2
- **Project period:** 2019-09-24 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940632

## Citation

> US National Institutes of Health, RePORTER application 10940632, Medicinal Chemistry and Radiochemistry Core (2U19NS110456-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10940632. Licensed CC0.

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