Structure-Guided Designed [¹⁸F]-labeled FAPI for Enhanced Hydrophilicity: From Preclinical to First-In-Human Study

Area of Science:

• Nuclear Medicine
• Radiochemistry
• Oncology

Background:

• Fibroblast activation protein (FAP) is highly expressed in cancer-associated fibroblasts.
• FAP is an attractive target for positron emission tomography (PET) imaging in oncology.
• Existing FAP-targeting agents may have limitations in terms of imaging characteristics or production.

Purpose of the Study:

• To develop and evaluate [18F]AlF-NOTA-GL01, an improved FAP-targeting PET imaging agent.
• To assess the radiochemical properties, binding affinity, and hydrophilicity of [18F]AlF-NOTA-GL01.
• To evaluate the in vivo performance of [18F]AlF-NOTA-GL01 in preclinical models and a first-in-human study.

Main Methods:

• Synthesis and radiolabeling of [18F]AlF-NOTA-GL01 using an Al[18F]-NOTA platform.
• Determination of radiochemical purity, FAP binding affinity (IC50), and hydrophilicity (LogD).
• PET imaging studies in A549-hFAP xenografts and a first-in-human study, including biodistribution and effective dose calculation. Comparison with [18F]FDG and [18F]FAPI-42.

Main Results:

• [18F]AlF-NOTA-GL01 was obtained with high radiochemical purity (>95%) and high FAP binding affinity (IC50 = 2.94 nM).
• Preclinical PET imaging demonstrated high tumor uptake (7.45 ± 2.34%ID/g at 60 min), rapid renal clearance, and low background.
• The first-in-human study showed persistent tumor uptake to 120 min, favorable dosimetry (0.03 ± 0.01 mSv/MBq), and superior target-to-background ratios compared to [18F]FDG and [18F]FAPI-42.

Conclusions:

• [18F]AlF-NOTA-GL01 is a promising FAP-targeting PET imaging agent with high affinity and excellent imaging properties.
• The agent exhibits favorable pharmacokinetics, including rapid clearance and low background uptake.
• The results support the clinical translation potential of [18F]AlF-NOTA-GL01 for improved cancer imaging.