Cyclohexanediamine Triazole (CHDT) Functionalization Enables Labeling of Target Molecules with Al¹⁸F/⁶⁸Ga/¹¹¹In

Area of Science:

• Radiochemistry and Medicinal Chemistry
• Molecular Imaging and Radiopharmacology

Background:

• Al¹⁸F-labeling offers a one-step method for radiofluorinated biomolecules, with (±)-H₂RESCA enabling ambient temperature labeling.
• The application of (±)-H₂RESCA for small molecules and peptides remains less explored compared to proteins.

Purpose of the Study:

• To develop a novel chelating unit for late-stage functionalization of biomolecules via click chemistry.
• To evaluate the utility of the new moiety for labeling with Al¹⁸F, ⁶⁸Ga, and ¹¹¹In.
• To assess the in vitro and in vivo performance of novel radiolabeled PSMA inhibitors for molecular imaging.

Main Methods:

• Introduction of an alkyne moiety into an acyclic pentadentate ligand to create the cyclohexanediamine triazole (CHDT) moiety.
• Synthesis of three novel CHDT-functionalized PSMA inhibitors.
• Radiolabeling with Al¹⁸F, ⁶⁸Ga, and ¹¹¹In, followed by in vitro characterization, stability studies in human serum, and in vivo PET imaging in a mouse model.

Main Results:

• The CHDT moiety demonstrated stable complexation of Al¹⁸F, ⁶⁸Ga, and ¹¹¹In.
• All radiometal complexes exhibited high kinetic inertness in vitro.
• Al[¹⁸F]F-CHDT-PSMA-1 showed comparable in vivo performance to [¹⁸F]PSMA-1007, with superior tumor-to-blood and tumor-to-muscle ratios.

Conclusions:

• The novel CHDT moiety is suitable for functionalization and radiolabeling of small molecules and peptides with Al¹⁸F, ⁶⁸Ga, and ¹¹¹In.
• The triazole ring appears to confer favorable pharmacokinetic properties for molecular imaging.
• This approach advances radiolabeling strategies for developing new diagnostic and therapeutic agents.