PT  - JOURNAL ARTICLE
AU  - Ye, Jiajun
AU  - Li, Xiang
AU  - Zhang, Mingru
AU  - Yang, Weidong
AU  - Kang, Fei
AU  - Wang, Jing
TI  - <strong>First-in-human PET imaging of KRAS p.G12C mutation status in NSCLC and CRC patients using 18F-AMG510</strong>
DP  - 2023 Jun 01
TA  - Journal of Nuclear Medicine
PG  - P340--P340
VI  - 64
IP  - supplement 1
4099  - http://jnm.snmjournals.org/content/64/supplement_1/P340.short
4100  - http://jnm.snmjournals.org/content/64/supplement_1/P340.full
SO  - J Nucl Med2023 Jun 01; 64
AB  - P340 Introduction: Kirsten rat sarcoma (KRAS) mutation would consecutively activate downstream oncoprotein pathway, thereby promoting tumor growth and survival. It is considered a key predictor of the efficacy of EGFR-targeted therapy in lung cancer, colorectal cancer and other tumors, and is included in guidelines such as National Comprehensive Cancer Network (NCCN). Therefore, accurate detection of KRAS mutations is a significant clinical need for precision cancer diagnosis and treatment. In this study, we sought to develop a PET tracer based on newly FDA-approved KRASG12C targeted drug AMG510 (Sotorasib), and to investigate its translational potential for noninvasive screening of KRASG12C mutation in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC) patients.Methods: 18F-AMG510 was synthesized based on AMG510 through modifying the quinazolinone structure with polyethylene glycol chain. The binding affinity of 18F-AMG510 was assessed by molecular docking, and further verified by cell uptake (H358: KRASG12C mutation; A549: non-KRASG12C mutation) study and micro-PET/CT imaging study on tumor bearing mice. Five healthy volunteers were enrolled for investigating the safety, biodistribution and dosimetry of 18F-AMG510. Subsequently, 14 NSCLC or CRC patients with or without KRASG12C mutation underwent 18F-AMG510 and 18F-FDG PET/CT imaging. SUVmax of tumor uptake of 18F-AMG510 was quantified and compared between patients with KRASG12C mutation and non-KRASG12C mutation.Results: 18F-AMG510 was successfully prepared with high radiochemical yield and high radiochemical purity. Molecular docking assay revealed F-AMG510 bind with KRASG12C protein. 18F-AMG510 uptake in H358 was significantly higher than A549, and decreased by pretreatment with AMG510 (H358 vs. A549: 3.22 ± 0.28% vs. 2.50 ± 0.25%, p < 0.05, block: 2.06 ± 0.13%, p < 0.01). Similar results were observed in tumor bearing mice PET imaging study (H358 vs. A549: 3.93 ± 0.24 vs.2.47 ± 0.26 % ID/g, p<0.01; block: 2.89 ± 0.29% ID/g, p < 0.05). 18F-AMG510 was safe in human, and it was primarily excreted by gallbladder and intestine. The effective absorbed dose was comparable to that of 18F-FDG. The accumulation of 18F-AMG510 at KRASG12C mutated tumors was significantly higher than non- KRASG12C mutation tumors (SUVmax: 3.73 ± 0.58 vs. 2.39 ± 0.22, p < 0.01) in NSCLC and CRC patients. Conclusions: 18F-AMG510 is a safe and promising PET tracer for clinically non-invasive imaging of KRASG12C mutation status in NSCLC and CRC patients. This study provided a new method for accurate non-invasive screening of tumor KRASG12C mutation, be valuable in achieving precise cancer diagnosis and treatment, and provide a reference for clinical translation studies of other KRASG12C probes.