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Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.

Publication ,  Journal Article
Zhou, Z; Zalutsky, MR; Chitneni, SK
Published in: Mol Pharm
October 4, 2021

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.

Duke Scholars

Published In

Mol Pharm

DOI

EISSN

1543-8392

Publication Date

October 4, 2021

Volume

18

Issue

10

Start / End Page

3871 / 3881

Location

United States

Related Subject Headings

  • para-Aminobenzoates
  • Pyrrolidines
  • Proto-Oncogene Proteins c-mdm2
  • Positron-Emission Tomography
  • Pharmacology & Pharmacy
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
  • Male
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zhou, Z., Zalutsky, M. R., & Chitneni, S. K. (2021). Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation. Mol Pharm, 18(10), 3871–3881. https://doi.org/10.1021/acs.molpharmaceut.1c00531
Zhou, Zhengyuan, Michael R. Zalutsky, and Satish K. Chitneni. “Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.Mol Pharm 18, no. 10 (October 4, 2021): 3871–81. https://doi.org/10.1021/acs.molpharmaceut.1c00531.
Zhou Z, Zalutsky MR, Chitneni SK. Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation. Mol Pharm. 2021 Oct 4;18(10):3871–81.
Zhou, Zhengyuan, et al. “Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.Mol Pharm, vol. 18, no. 10, Oct. 2021, pp. 3871–81. Pubmed, doi:10.1021/acs.molpharmaceut.1c00531.
Zhou Z, Zalutsky MR, Chitneni SK. Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation. Mol Pharm. 2021 Oct 4;18(10):3871–3881.
Journal cover image

Published In

Mol Pharm

DOI

EISSN

1543-8392

Publication Date

October 4, 2021

Volume

18

Issue

10

Start / End Page

3871 / 3881

Location

United States

Related Subject Headings

  • para-Aminobenzoates
  • Pyrrolidines
  • Proto-Oncogene Proteins c-mdm2
  • Positron-Emission Tomography
  • Pharmacology & Pharmacy
  • Neoplasm Transplantation
  • Mice, Nude
  • Mice
  • Male
  • Humans