First-in-Humans PET Imaging of KRASG12C Mutation Status in Non-Small Cell Lung and Colorectal Cancer Patients Using [18F]PFPMD.

Kirsten rat sarcoma (KRAS) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRAS^G12C oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the KRAS^G12C mutation in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. Methods: [¹⁸F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure. The binding selectivity and imaging potential of [¹⁸F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: KRAS^G12C mutation; A549: non-KRAS^G12C mutation) studies, as well as by a small-animal PET/CT imaging study on tumor-bearing mice. Five healthy volunteers were enrolled to assess the safety, biodistribution, and dosimetry of [¹⁸F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the KRAS^G12C mutation underwent [¹⁸F]PFPMD and [¹⁸F]FDG PET/CT imaging. The SUV_max of tumor uptake of [¹⁸F]PFPMD was measured and compared between patients with and without the KRAS^G12C mutation. Results: [¹⁸F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [¹⁸F]PFPMD selectively binds to the KRAS^G12C protein. [¹⁸F]PFPMD uptake was significantly higher in H358 than in A549 and was 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 on PET imaging (H358 vs. A549: 3.93% ± 0.24% vs. 2.47% ± 0.26% injected dose/g, P < 0.01; block: 2.89% ± 0.29% injected dose/g; P < 0.05). [¹⁸F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [¹⁸F]FDG. The accumulation of [¹⁸F]PFPMD in KRAS^G12C mutation tumors was significantly higher than that in non-KRAS^G12C mutation tumors (SUV_max: 3.73 ± 0.58 vs. 2.39 ± 0.22, P < 0.01) in NSCLC and CRC patients. Conclusion: [¹⁸F]PFPMD is a safe and promising PET tracer for noninvasive screening of the KRAS^G12C mutation status in NSCLC and CRC patients.