PT - JOURNAL ARTICLE AU - Li, Xiang AU - Ye, Jiajun AU - Wang, Jingyi AU - Quan, Zhiyong AU - Li, Guiyu AU - Ma, Wenhui AU - Zhang, Mingru AU - Yang, Weidong AU - Wang, Junling AU - Ma, Taoqi AU - Kang, Fei AU - Wang, Jing TI - First-in-Humans PET Imaging of <em>KRAS<sup>G12C</sup></em> Mutation Status in Non–Small Cell Lung and Colorectal Cancer Patients Using [<sup>18</sup>F]PFPMD AID - 10.2967/jnumed.123.265715 DP - 2023 Dec 01 TA - Journal of Nuclear Medicine PG - 1880--1888 VI - 64 IP - 12 4099 - http://jnm.snmjournals.org/content/64/12/1880.short 4100 - http://jnm.snmjournals.org/content/64/12/1880.full SO - J Nucl Med2023 Dec 01; 64 AB - Kirsten rat sarcoma (KRAS) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRASG12C oncoprotein–targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the KRASG12C 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: KRASG12C mutation; A549: non-KRASG12C 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 KRASG12C mutation underwent [18F]PFPMD and [18F]FDG PET/CT imaging. The SUVmax of tumor uptake of [18F]PFPMD was measured and compared between patients with and without the KRASG12C 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 KRASG12C 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 &lt; 0.05; block: 2.06% ± 0.13%, P &lt; 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 &lt; 0.01; block: 2.89% ± 0.29% injected dose/g; P &lt; 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 KRASG12C mutation tumors was significantly higher than that in non-KRASG12C mutation tumors (SUVmax: 3.73 ± 0.58 vs. 2.39 ± 0.22, P &lt; 0.01) in NSCLC and CRC patients. Conclusion: [18F]PFPMD is a safe and promising PET tracer for noninvasive screening of the KRASG12C mutation status in NSCLC and CRC patients.