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

Zhou, Zhengyuan

Zalutsky, Michael R

Chitneni, Satish K

2021-10-01T14:03:46Z

2021-10-01T14:03:46Z

2021-09-15

2021-10-01T14:03:45Z

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 (K_d) 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.

1543-8384

1543-8392

https://hdl.handle.net/10161/23875

eng

American Chemical Society (ACS)

Molecular pharmaceutics

10.1021/acs.molpharmaceut.1c00531

AMG232

MDM2

PET

RG7388

SJSA-1

fluorine-18

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

Journal article

Zalutsky, Michael R|0000-0002-5456-0324

Chitneni, Satish K|0000-0003-1183-2286

School of Medicine

Duke Cancer Institute

Duke Institute for Brain Sciences

Radiology

Duke

Institutes and Centers

University Institutes and Centers

Institutes and Provost's Academic Units

Clinical Science Departments

Pathology

Radiation Oncology

Published