Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation.
dc.contributor.author | Zhou, Zhengyuan | |
dc.contributor.author | Zalutsky, Michael R | |
dc.contributor.author | Chitneni, Satish K | |
dc.date.accessioned | 2021-10-01T14:03:46Z | |
dc.date.available | 2021-10-01T14:03:46Z | |
dc.date.issued | 2021-09-15 | |
dc.date.updated | 2021-10-01T14:03:45Z | |
dc.description.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. | |
dc.identifier.issn | 1543-8384 | |
dc.identifier.issn | 1543-8392 | |
dc.identifier.uri | ||
dc.language | eng | |
dc.publisher | American Chemical Society (ACS) | |
dc.relation.ispartof | Molecular pharmaceutics | |
dc.relation.isversionof | 10.1021/acs.molpharmaceut.1c00531 | |
dc.subject | AMG232 | |
dc.subject | MDM2 | |
dc.subject | PET | |
dc.subject | RG7388 | |
dc.subject | SJSA-1 | |
dc.subject | fluorine-18 | |
dc.title | Fluorine-18 Labeling of the MDM2 Inhibitor RG7388 for PET Imaging: Chemistry and Preliminary Evaluation. | |
dc.type | Journal article | |
duke.contributor.orcid | Zalutsky, Michael R|0000-0002-5456-0324 | |
duke.contributor.orcid | Chitneni, Satish K|0000-0003-1183-2286 | |
pubs.organisational-group | School of Medicine | |
pubs.organisational-group | Duke Cancer Institute | |
pubs.organisational-group | Duke Institute for Brain Sciences | |
pubs.organisational-group | Radiology | |
pubs.organisational-group | Duke | |
pubs.organisational-group | Institutes and Centers | |
pubs.organisational-group | University Institutes and Centers | |
pubs.organisational-group | Institutes and Provost's Academic Units | |
pubs.organisational-group | Clinical Science Departments | |
pubs.organisational-group | Pathology | |
pubs.organisational-group | Radiation Oncology | |
pubs.publication-status | Published |
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