A Novel Arene Trifluoromethyl-Based ¹⁸F-Labeling Strategy for Enhanced Biomolecular Tracer Development in PET...

Area of Science:

• Radiochemistry and Nuclear Medicine
• Molecular Imaging
• Bioconjugation Chemistry

Background:

• Biologically active molecules are ideal for PET imaging due to target affinity and biocompatibility.
• Fluorine-18 (¹⁸F) is a preferred radionuclide for PET imaging.
• Traditional ¹⁸F-labeling methods are often harsh, compromising biomolecule integrity.

Purpose of the Study:

• To develop a mild and efficient ¹⁸F-labeling strategy for advanced biomolecular PET tracers.
• To synthesize and evaluate a novel clickable ¹⁸F-labeled synthon for CuAAC conjugation.
• To demonstrate the utility of this method for labeling various biomolecules and in vivo PET imaging.

Main Methods:

• Developed a novel clickable ¹⁸F-labeled synthon, 1-ethynyl-3-([¹⁸F]trifluoromethyl)-5-(trifluoromethyl)benzene ([¹⁸F]1), via ¹⁸F/¹⁹F isotope exchange.
• Utilized copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) for conjugation with azide-modified biomolecules (glucose derivatives, RGD peptides, phospholipids).
• Performed PET imaging in U87 MG, 4T1, and BT474 xenograft models to assess tumor uptake and specificity.

Main Results:

• The ¹⁸F-labeled synthon ([¹⁸F]1) was prepared with a radiochemical yield of 17.2 ± 3.9%.
• Efficient and chemoselective CuAAC conjugation was achieved under mild conditions.
• PET imaging demonstrated favorable tumor uptake and high binding specificity for labeled RGD peptides ([¹⁸F]5a and [¹⁸F]5b) in xenograft models, with [¹⁸F]5b showing superior accumulation.

Conclusions:

• The developed isotope exchange-based CuAAC labeling strategy streamlines PET tracer synthesis.
• This method effectively preserves biomolecule integrity, enabling the development of advanced PET tracers.
• The strategy offers a versatile platform for molecular imaging and pretargeting applications.