RT Journal Article
SR Electronic
T1 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
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1880
OP 1888
DO 10.2967/jnumed.123.265715
VO 64
IS 12
A1 Li, Xiang
A1 Ye, Jiajun
A1 Wang, Jingyi
A1 Quan, Zhiyong
A1 Li, Guiyu
A1 Ma, Wenhui
A1 Zhang, Mingru
A1 Yang, Weidong
A1 Wang, Junling
A1 Ma, Taoqi
A1 Kang, Fei
A1 Wang, Jing
YR 2023
UL http://jnm.snmjournals.org/content/64/12/1880.abstract
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.