Theranostics · 2026
Development and in vivo evaluation of 18F-labeled PET tracers covalently targeting KRAS-G12C for noninvasive cancer diagnosis and therapy monitoring.
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Willmann Michael, Bankstahl Jens P, Bengel Frank M, Drechsler Christine, Esdar Christina, Gläser Kathrin, Lopez Andrea U, Ross Tatjana, Schieferstein Hanno, Ross Tobias L
Аннотация
RATIONALE: Mutations in the KRAS gene are some of the most frequent drivers in cancer, including non-small cell lung and colorectal cancer. Covalent inhibitors such as adagrasib, targeting the inactive, GDP-bound form of KRAS-G12C, have shown clinical efficacy but patient selection still depends on invasive biopsies. This study aimed to develop novel fluorine-18 labeled KRAS-G12C inhibitors for noninvasive positron emission tomography (PET) imaging of KRAS mutation status.
METHODS: Three KRAS-G12C inhibitors were synthesized by modifying the adagrasib scaffold to allow for radiofluorination. Compounds were evaluated for target affinity and specificity using pERK inhibition assays in KRAS-G12C positive MiaPaCa-2 cells and KRAS protein binding assays. Finally, in vivo PET imaging and biodistribution studies were performed in MiaPaCa-2 xenograft-bearing mice under baseline and blocking conditions to assess tumor uptake, specificity, and tracer pharmacokinetics.
RESULTS: In µPET, the tracers showed distinct tumor uptake and biodistribution profiles. Among them, [18F]KRAS490 demonstrated the most promising characteristics, with clear tumor accumulation that was significantly reduced under blocking conditions, indicating specific target binding. In contrast, [18F]KRAS8125 and [18F]KRAS3776 showed limited or non-replaceable tumor uptake. The tracers showed varied clearance patterns, with [18F]KRAS490 showing combined hepatobiliary and renal clearance. Notably, [18F]KRAS490 also entered the brain, suggesting the potential for central nervous system imaging.
CONCLUSIONS: [18F]KRAS490 showed specific, blockable tumor uptake and favorable pharmacokinetics, making it a promising tracer for noninvasive imaging of KRAS-G12C mutant tumors. Its ability to penetrate the CNS supports potential application in imaging both peripheral and brain lesions.
METHODS: Three KRAS-G12C inhibitors were synthesized by modifying the adagrasib scaffold to allow for radiofluorination. Compounds were evaluated for target affinity and specificity using pERK inhibition assays in KRAS-G12C positive MiaPaCa-2 cells and KRAS protein binding assays. Finally, in vivo PET imaging and biodistribution studies were performed in MiaPaCa-2 xenograft-bearing mice under baseline and blocking conditions to assess tumor uptake, specificity, and tracer pharmacokinetics.
RESULTS: In µPET, the tracers showed distinct tumor uptake and biodistribution profiles. Among them, [18F]KRAS490 demonstrated the most promising characteristics, with clear tumor accumulation that was significantly reduced under blocking conditions, indicating specific target binding. In contrast, [18F]KRAS8125 and [18F]KRAS3776 showed limited or non-replaceable tumor uptake. The tracers showed varied clearance patterns, with [18F]KRAS490 showing combined hepatobiliary and renal clearance. Notably, [18F]KRAS490 also entered the brain, suggesting the potential for central nervous system imaging.
CONCLUSIONS: [18F]KRAS490 showed specific, blockable tumor uptake and favorable pharmacokinetics, making it a promising tracer for noninvasive imaging of KRAS-G12C mutant tumors. Its ability to penetrate the CNS supports potential application in imaging both peripheral and brain lesions.