Click Chemistry for 18F-Labeling of RGD Peptides and microPET Imaging of Tumor Integrin αvβ3 Expression

The cell adhesion molecule integrin αvβ3 plays a key role in tumor angiogenesis and metastasis. A series of 18F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine reactive prosthetic groups. In this study, we report the use of the Cu(I)-catalyzed Huisgen cycloaddition, also known as a click reaction, to label RGD peptides with 18F by forming 1,2,3-triazoles. Nucleophilic fluorination of a toluenesulfonic alkyne provided 18F-alkyne in high yield (nondecay-corrected yield: 65.0 ± 1.9%, starting from the azeotropically dried 18F-fluoride), which was then reacted with an RGD azide (nondecay-corrected yield: 52.0 ± 8.3% within 45 min including HPLC purification). The 18F-labeled peptide was subjected to microPET studies in murine xenograft models. Murine microPET experiments showed good tumor uptake (2.1 ± 0.4%ID/g at 1 h postinjection (p.i.)) with rapid renal and hepatic clearance of 18F-fluoro-PEG-triazoles-RGD2 (18F-FPTA-RGD2) in a subcutaneous U87MG glioblastoma xenograft model (kidney 2.7 ± 0.8%ID/g; liver 1.9 ± 0.4%ID/g at 1 h p.i.). Metabolic stability of the newly synthesized tracer was also analyzed (intact tracer ranging from 75% to 99% at 1 h p.i.). In brief, the new tracer 18F-FPTA-RGD2 was synthesized with high radiochemical yield and high specific activity. This tracer exhibited good tumor-targeting efficacy and relatively good metabolic stability, as well as favorable in vivo pharmacokinetics. This new 18F labeling method based on click reaction may also be useful for radiolabeling of other biomolecules with azide groups in high yield.