Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.
Abstract
RG7388 (Idasanutlin) is a potent inhibitor of oncoprotein murine double minute 2 (MDM2).
Herein we investigated the feasibility of developing 18F-labeled RG7388 as a radiotracer for imaging MDM2 expression in tumors with positron
emission tomography (PET). Two fluorinated analogues of RG7388, 6 and 7, were synthesized by attaching a fluoronicotinyl moiety to RG7388 via a polyethylene
glycol (PEG3) or a propyl linker. The inhibitory potency (IC50) of 6 and 7 against MDM2 was determined by a fluorescence polarization (FP)-based assay. Next,
compound 6 was labeled with 18F using a trimethylammonium triflate precursor to obtain [18F]FN-PEG3-RG7388 ([18F]6), and its properties were evaluated in MDM2 expressing wild-type p53 tumor cell lines
(SJSA-1 and HepG2) in vitro and in tumor xenografts in vivo. The FP assays revealed
an IC50 against MDM2 of 119 nM and 160 nM for 6 and 7, respectively. 18F-labeling of 6 was achieved in 50.3 ± 7.5% radiochemical yield. [18F]6 exhibited a high uptake (∼70% of input dose) and specificity in SJSA-1 and HepG2
cell lines. Saturation binding assays revealed a binding affinity (Kd) of 128 nM for [18F]6 on SJSA-1 cells. In mice, [18F]6 showed fast clearance from blood with a maximum tumor uptake of 3.80 ± 0.85% injected
dose per gram (ID/g) in HepG2 xenografts at 30 min postinjection (p.i.) and 1.32 ±
0.32% ID/g in SJSA-1 xenografts at 1 h p.i. Specificity of [18F]6 uptake in tumors was demonstrated by pretreatment of mice with SJSA-xenografts with
a blocking dose of RG7388 (35 mg/kg body weight, i.p.). In vivo stability studies
in mice using HPLC showed ∼60% and ∼30% intact [18F]6 remaining in plasma at 30 min and 1 h p.i., respectively, with the remaining activity
attributed to polar peaks. Our results suggest that RG7388 is a promising molecular
scaffold for 18F-labeled probe development for MDM2. Additional labeling strategies and functionalizing
locations on RG7388 are under development to improve binding affinity and in vivo
stability of the 18F-labeled compound to make it more amenable for PET imaging of MDM2 in vivo.
Type
Journal articlePermalink
https://hdl.handle.net/10161/23875Published Version (Please cite this version)
10.1021/acs.molpharmaceut.1c00531Publication Info
Zhou, Zhengyuan; Zalutsky, Michael R; & Chitneni, Satish K (2021). Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary
Evaluation. Molecular pharmaceutics. 10.1021/acs.molpharmaceut.1c00531. Retrieved from https://hdl.handle.net/10161/23875.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
Collections
More Info
Show full item recordScholars@Duke
Satish K. Chitneni
Associate Professor in Radiology
PET radiochemistry and molecular imaging New radiopharmaceutical development for CNS
imaging and cancers Pre-clinical PET/CT imaging
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Michael Rod Zalutsky
Jonathan Spicehandler, M.D. Distinguished Professor of Neuro Oncology, in the School
of Medicine
The overall objective of our laboratory is the development of novel radioactive compounds
for improving the diagnosis and treatment of cancer. This work primarily involves
radiohalo-genation of biomolecules via site-specific approaches, generally via demetallation
reactions. Radionuclides utilized for imaging include I-123, I-124 and F-18, the later
two being of particular interest because they can be used for the quantification of
biochemical and physiological processes in the living huma
Alphabetical list of authors with Scholars@Duke profiles.

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info