Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant

Abstract

Although KRAS has been an important target for many cancers, direct inhibition of oncogenic RAS remains challenging. Until recently, covalent KRAS G12C-specific inhibitors have been developed and progressed to the clinics. Nevertheless, not all patients benefit from these covalent inhibitors. At present, identification of candidates for this treatment requires tissue biopsies and gene sequencing, which are invasive, time-consuming, and could be of insufficient quality and limited predictive value owing to tumor heterogeneity. The use of noninvasive molecular imaging techniques such as PET and SPECT for spying KRAS G12C mutation in tumors provide a promising strategy for circumventing these hurdles. In the present study, based on the covalent G12C-specific inhibitor ARS-1620, we sought to develop radiolabeled small molecules for direct imaging of the KRAS mutation status in tumors. [131I]­I-ARS-1620 and [18F]­F-ARS-1620 were successfully prepared with high radiochemical yield, radiochemical purity, and molar activity. In vitro and in vivo studies have demonstrated the affinity, specificity, and capacity of [131I]­I-ARS-1620 for direct imaging of the oncogenic KRAS G12C mutant. This initial attempt allows us to directly screen the KRAS G12C mutant for the first time in vivo.

Combined Probe Strategy to Increase the Enzymatic Digestion Rate and Accelerate the Renal Radioactivity Clearance of Peptide Radiotracers

“…This is probably due to the preference of enzymes to substrates. As reported in our previous study, compared with Boc-MVK-Dde, Boc-MFK-Dde is an optimal substrate for NEP, which was further confirmed by the K m and V max of these two model compounds, with NEP evaluated in this study.…”

Preclinical Evaluation of 131I/18F-Labeled Covalent Small-Molecule Inhibitors for STING Status Imaging

“…Protein binding assays were performed as described in previous works. , The tracers ([ 131 I]­I-NFIP and [ 18 F]­F-NFEP) were dissolved in HEPES buffer (10 mM, pH = 7.4) with a radioactivity concentration of 3.7 MBq/mL. 100 μL of the radioligand solution was added to a reaction tube containing 4 μg of protein (mouse STING protein or HSA) and then incubated at 37 °C for 1 h. The reaction was stopped by adding 10 μL of formic acid to adjust pH < 7.0.…”