Preclinical Evaluation of a Radiolabeled Pan-RAF Inhibitor for RAF-Specific PET/CT Imaging

Area of Science:

• Oncology
• Radiochemistry
• Molecular Imaging

Background:

• RAS-RAF pathway abnormalities drive many solid tumors, making RAF inhibitors key targeted therapies.
• Naporafenib (LXH-254) is an FDA Fast Track Qualified pan-RAF inhibitor.
• Noninvasive methods are needed to screen patients for RAF-targeted therapy susceptibility.

Purpose of the Study:

• To develop an 18F-labeled molecular probe ([18F]F-LXH-254) based on LXH-254 for PET imaging.
• To assess the tracer's ability to image tumors overexpressing RAF.
• To evaluate its utility in patient screening for RAF-targeted therapy.

Main Methods:

• LXH-254 was modified with TsO-PEG3-OTs to create a precursor (LXH-254-OTs).
• A nucleophilic substitution reaction with 18F yielded the radiotracer [18F]F-LXH-254.
• Micro-PET imaging was performed in tumor-bearing mice to evaluate tracer uptake and specificity.

Main Results:

• [18F]F-LXH-254 demonstrated good molar activity (7.16 ± 0.81 GBq/μmol), radiochemical purity (>95%), and stability.
• Micro-PET imaging showed significant radioactivity accumulation in tumors, which was blocked by excess unlabeled LXH-254.
• This confirms the tracer's affinity and specificity for targeting RAF in vivo.

Conclusions:

• [18F]F-LXH-254 is a promising radiotracer for PET imaging of RAF-driven tumors.
• It can aid in screening patients for RAF-targeted therapy and monitoring treatment response.
• This represents the first 18F-labeled RAF-specific radiotracer for clinical applications.