18 F-ARS-1620: Radiosynthesis and therapy response evaluation of a KRAS G12C -targeted PET tracer in tumor-bearing mice

Background: The Kirsten rat sarcoma virus oncogene homologue (KRAS) is the most frequently mutated gene in non-small cell lung cancer (NSCLC), and the long-standing “undruggable” challenge of this molecular target was finally overcome in recent years. Discrepancy between genetic mutations and protein expression abundance has led to the emergence of in vivo identification of KRAS-positive mutation subtypes as a critical prerequisite for precise treatment. Methods: In this study, a KRAS G12C -targeted positron emission tomography (PET) molecular imaging tracer, 18 F-ARS-1620, was developed by labeling the small-molecule inhibitor ARS-1620 analogue with 18 F. The stability and physicochemical properties of 18 F-ARS-1620 were assessed using radioactive high-performance liquid chromatography (HPLC). The targeting specificity, in vivo detection capability of the KRAS G12C mutation, and therapeutic response monitoring efficacy of 18 F-ARS-1620 were evaluated in NSCLC models overexpressing KRAS G12C . Results: 18 F-ARS-1620 was prepared with a high radiochemical yield and purity. The KRAS G12C -high H2122 cell showed significantly higher uptake of 18 F-ARS-1620 than the KRAS G12C -low H460 cell (2.18 ± 0.24 %ID vs . 0.46 ± 0.07 %ID; n = 3, P <0.001), and a consistent trend of the tracer's specificity was also found in vivo , with 18 F-ARS-1620 accumulating more in H2122 tumors than in H460 tumors (6.33 ± 0.31 %ID/g vs . 3.55 ± 0.13 %ID/g at 60 min, n = 3, P <0.01). For monitoring therapeutic efficacy, H2122 tumor-bearing mice were administered KRAS G12C small-molecule inhibitors (ARS-1620 or AMG510), and tumor growth was significantly inhibited in both treatment groups. PET/CT imaging was performed on days 0, 7, and 14 to monitor therapeutic efficacy, and a significant reduction of 18 F-ARS-1620 uptake in H2122 tumors was observed (%ID/g at day 14: control, 5.39 ± 0.42; AMG510, 3.39 ± 0.24, n = 5, P <0.001). Survival curve analysis demonstrated that reduced tracer uptake was associated with prolonged survival in the treatment group compared to the control group ( P <0.05). These in vivo findings were further corroborated by ex vivo biodistribution analysis and quantitative autoradiography. Conclusion: 18 F-ARS-1620 PET enabled noninvasive visualization of the KRAS G12C mutation in NSCLC models and monitoring of the therapeutic efficacy of KRAS inhibitors. This molecular imaging approach holds clinical potential for stratifying patients based on KRAS G12C status and guiding precision treatment strategies throughout the management of NSCLC.