Comparison Study of Two Differently Clicked ¹⁸F-Folates-Lipophilicity Plays a Key Role

Area of Science:

• Radiopharmaceutical chemistry
• Molecular imaging
• Oncology

Background:

• Folate-based radiopharmaceuticals are crucial for SPECT and PET imaging.
• A need exists for effective 18F-labeled folates for clinical PET imaging.
• Click chemistry offers versatile methods for radiopharmaceutical development.

Purpose of the Study:

• To synthesize and evaluate two novel 18F-folates using strain-promoted and copper-catalyzed click chemistry.
• To investigate the impact of click chemistry methods on folate lipophilicity and pharmacokinetics.
• To assess the potential of these 18F-folates for folate receptor (FR)-targeted PET imaging.

Main Methods:

• Synthesis of two novel 18F-folates: 18F-Ala-folate (copper-catalyzed) and 18F-DBCO-folate (strain-promoted).
• In vitro stability and folate receptor binding assays.
• Lipophilicity (logD) determination.
• In vitro cell internalization studies.
• In vivo PET imaging studies in tumor-bearing models.

Main Results:

• Both 18F-folates demonstrated stability in human serum albumin and high affinity for the folate receptor.
• 18F-DBCO-folate exhibited higher lipophilicity (logD = 0.6), leading to increased non-specific binding and poor tumor visualization.
• 18F-Ala-folate, with reduced lipophilicity (logD = -1.4), showed improved in vivo performance and clear visualization of FR-positive tumors.
• High radiochemical yield and purity were achieved for 18F-Ala-folate.

Conclusions:

• Copper-catalyzed click chemistry yielded 18F-Ala-folate with favorable pharmacokinetic properties for PET imaging.
• Reduced lipophilicity is critical for effective folate-based PET imaging agent performance.
• 18F-Ala-folate is a promising candidate for clinical folate receptor-targeted PET imaging.