First-in-Humans PET Imaging of<i>KRAS<sup>G12C</sup></i>Mutation Status in Non–Small Cell Lung and Colorectal Cancer Patients Using [<sup>18</sup>F]PFPMD
Xiang Li, Jiajun Ye, Jingyi Wang, Zhiyong Quan, Guiyu Li, Wenhui Ma, Mingru Zhang, Weidong Yang, Junling Wang, Taoqi Ma, Fei Kang, Jing Wang
Abstract
Kirsten rat sarcoma (<i>KRAS</i>) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRAS<sup>G12C</sup> oncoprotein–targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the <i>KRAS<sup>G12C</sup></i> mutation in non–small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. <b>Methods:</b> [<sup>18</sup>F]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 [<sup>18</sup>F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: <i>KRAS<sup>G12C</sup></i> mutation; A549: non-<i>KRAS<sup>G12C</sup></i> 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 [<sup>18</sup>F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the <i>KRAS<sup>G12C</sup></i> mutation underwent [<sup>18</sup>F]PFPMD and [<sup>18</sup>F]FDG PET/CT imaging. The SUV<sub>max</sub> of tumor uptake of [<sup>18</sup>F]PFPMD was measured and compared between patients with and without the <i>KRAS<sup>G12C</sup></i> mutation. <b>Results:</b> [<sup>18</sup>F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [<sup>18</sup>F]PFPMD selectively binds to the KRAS<sup>G12C</sup> protein. [<sup>18</sup>F]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%, <i>P</i> < 0.05; block: 2.06% ± 0.13%, <i>P</i> < 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, <i>P</i> < 0.01; block: 2.89% ± 0.29% injected dose/g; <i>P</i> < 0.05). [<sup>18</sup>F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [<sup>18</sup>F]FDG. The accumulation of [<sup>18</sup>F]PFPMD in <i>KRAS<sup>G12C</sup></i> mutation tumors was significantly higher than that in non-<i>KRAS<sup>G12C</sup></i> mutation tumors (SUV<sub>max</sub>: 3.73 ± 0.58 vs. 2.39 ± 0.22, <i>P</i> < 0.01) in NSCLC and CRC patients. <b>Conclusion:</b> [<sup>18</sup>F]PFPMD is a safe and promising PET tracer for noninvasive screening of the <i>KRAS<sup>G12C</sup></i> mutation status in NSCLC and CRC patients.