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Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the
Zhe Zhang1, Xiaobo Wang1, Jiajun Ye2
1Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
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.
Insights
Researchers developed novel radiolabeled tracers to noninvasively image KRAS G12C mutations in tumors. This breakthrough allows for direct in vivo screening of patients, overcoming limitations of traditional biopsies for targeted cancer therapy.
Area of Science:
- Oncology
- Molecular Imaging
- Radiochemistry
Background:
- Oncogenic KRAS mutations drive many cancers, but direct inhibition remains difficult.
- Covalent KRAS G12C inhibitors show promise, yet patient selection via invasive biopsies is challenging due to tumor heterogeneity.
- Noninvasive molecular imaging offers a potential solution for identifying patients eligible for KRAS G12C-targeted therapies.
Purpose of the Study:
- To develop radiolabeled small molecules for direct in vivo imaging of KRAS G12C mutations.
- To adapt the covalent KRAS G12C-specific inhibitor ARS-1620 into imaging agents.
Main Methods:
- Preparation of radiolabeled tracers [131I]I-ARS-1620 and [18F]F-ARS-1620.
- Assessment of radiochemical yield, purity, and molar activity.
- In vitro and in vivo evaluation of tracer performance, including affinity and specificity.
Main Results:
- Successfully synthesized [131I]I-ARS-1620 and [18F]F-ARS-1620 with high quality.
- [131I]I-ARS-1620 demonstrated significant affinity, specificity, and capacity for imaging KRAS G12C mutants in vitro and in vivo.
- The study represents the first in vivo direct screening of KRAS G12C mutations.
Conclusions:
- Radiolabeled ARS-1620 analogs are viable tools for molecular imaging of KRAS G12C.
- Noninvasive imaging of KRAS G12C status can improve patient selection for targeted therapies.
- This approach circumvents the limitations associated with traditional tissue biopsies.
