Strain–Promoted Copper-Free Click Chemistry for Efficient 18F–Labeling of Poly(ethylene glycol) Azides via Dibenzocyclooctyne Acid

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ABSTRACT

Positron emission tomography (PET) imaging relies on efficient radiolabeling strategies for the synthesis of biologically relevant tracers. In this study, we present a novel approach utilizing strain-promoted alkyne-azide cycloaddition (SPAAC) for the rapid and high-yielding ¹⁸F-labeling of poly(ethylene glycol) (PEG) azides using dibenzocyclooctyne acid (DIBAC). A nucleophilic fluorination reaction was performed on an N3-PEG mesylate precursor, yielding [¹⁸F]17 with a radiochemical yield of 45% (specific activity: 220 GBq/μmol) within 70 minutes, including HPLC purification. Subsequent bioorthogonal conjugation with DIBAC (3) under optimized conditions afforded the ¹⁸F-labeled triazole product [¹⁸F]3 in excellent radiochemical purity (>99%) and high yield (92%). Key advantages of this method include the elimination of cytotoxic copper catalysts, rapid reaction kinetics (complete within 30 min at room temperature), and compatibility with biomolecules. Systematic optimization revealed that even substoichiometric amounts of DIBAC (0.2 mg, 0.0006 mmol) achieved >96% conversion, minimizing excess reagent interference. The high specific activity (254.69 GBq/μmol) and efficiency of this approach underscore its potential for PET tracer development. This work demonstrates the feasibility of copper-free click chemistry for ¹⁸F-labeling, offering a robust platform for synthesizing radiotracers with applications in molecular imaging, drug development, and targeted diagnostics. The chemoselective and bioorthogonal nature of SPAAC ensures broad utility in labeling peptides, antibodies, and other bioactive molecules without compromising their physiological integrity.

Significance of the Study:

This study advances radiopharmaceutical chemistry by providing a robust, copper-free 18F-labeling platform. The SPAAC-based approach addresses cytotoxicity concerns of CuAAC while maintaining high efficiency and specificity. Its compatibility with biomolecules and short reaction time aligns with 18F’s half-life, enabling broader applications in PET imaging. The methodology’s scalability and mild conditions facilitate the labeling of peptides, antibodies, and other targeting vectors, offering a versatile tool for diagnostic and therapeutic radiopharmaceutical development in oncology and neurology.

Summary of the Study:

This work developed a copper-free 18F-labeling strategy using strain-promoted azide-alkyne cycloaddition (SPAAC) between dibenzocyclooctyne acid (DIBAC) and [18F]PEG-azide. The synthesis achieved high radiochemical yields (92%) and specific activity (254.69 GBq/µmol) within 90 minutes. Optimization studies demonstrated efficient labeling with substoichiometric DIBAC (0.2 mg). The method eliminates copper catalysts, ensuring biocompatibility, and offers rapid, chemoselective conjugation under mild conditions, making it suitable for PET tracer development.