# Flourine-18 labeled MDM2 antagonists for PET imaging

> **NIH NIH R21** · DUKE UNIVERSITY · 2021 · $225,803

## Abstract

ABSTRACT
The tumor suppressor protein p53 plays a critical role in protecting cells against oncogenic transformation.
Consistent with this role, nearly 50% of all human cancers have a mutation in the p53 gene, rendering the p53
protein inactive. In tumors that are wild-type p53, the p53 function is often inhibited by the overexpression of
its negative regulatory protein, murine double minute 2 (MDM2). Studies suggests that MDM2 is
overexpressed in several human cancers, including breast cancer, sarcomas and glioblastoma, although at
different rates. MDM2 interacts with p53 in a negative feedback loop and targets the p53 protein for
proteasomal degradation, thereby inhibiting the tumor suppressive function of p53 in wild-type p53 tumors.
Hence, inhibition of MDM2 with small molecule antagonists or other molecular scaffolds such as stapled
peptides is being pursued as a therapeutic strategy for activating the p53 pathway in wild-type p53 cancers.
Whilst the preclinical and the early clinical data have demonstrated the promise of this therapeutic approach,
recent phase 1 clinical trials with small molecule MDM2 antagonists have indicated significant association
between pre-treatment MDM2 expression levels and therapeutic response in patients with acute myeloid
leukemia. These data suggest the need for selecting appropriate patients for MDM2 inhibition therapies and
the potential usefulness of MDM2 as a predictive biomarker for MDM2 targeted therapies. One of the critical
barriers for such studies is the lack of a noninvasive method for determining MDM2 overexpression status in
tumors. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), the most commonly used
methods for assessing MDM2 gene amplification and MDM2 protein overexpression in tumors, respectively,
are invasive and do not permit monitoring the treatment response in vivo. To address these needs, we
propose to develop radiolabeled probes for imaging the MDM2 protein expression levels in tumors
noninvasively with positron emission tomography (PET), a highly sensitive molecular imaging technique.
Building on the preliminary data we obtained in support of the project, we will synthesize fluorine-18 labeled
compounds that bind to the MDM2 protein with high affinity (Aim 1). The labeled compounds will be evaluated
for their potential to bind on MDM2 expressing tumors cells in vitro (Aim 2) and in mouse models of breast
cancer and soft tissue sarcomas in vivo (Aim 3) to identify a lead molecule for MDM2 imaging with PET. To
the best of our knowledge, this project would be the first study to develop PET imaging agents for the
oncoprotein MDM2. Successful development of a PET imaging approach for the MDM2 protein will provide a
valuable tool for studying MDM2-p53 biology in vivo and for investigation of novel therapies targeting MDM2 in
wild-type p53 cancers.

## Key facts

- **NIH application ID:** 10102215
- **Project number:** 5R21CA241823-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Satish K. Chitneni
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $225,803
- **Award type:** 5
- **Project period:** 2020-02-10 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102215

## Citation

> US National Institutes of Health, RePORTER application 10102215, Flourine-18 labeled MDM2 antagonists for PET imaging (5R21CA241823-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10102215. Licensed CC0.

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