Click chemistry for 18F-labeling of RGD peptides and microPET Imaging of tumor integrin αvβ3 expression

The cell adhesion molecule integrin (alpha(v)beta(3) plays a key role in tumor angiogenesis and metastasis. A series of F-18-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 F-18 by forming 1,2,3-triazoles. Nucleophilic fluorination of a toluenesulfonic alkyne provided F-18-alkyne in high yield (nondecay-corrected yield: 65.0 +/- 1.9%, starting from the azeotropically dried F-18-fluoride), which was then reacted with an RGD azide (nondecay-corrected yield: 52.0 +/- 8.3% within 45 min including HPLC purification). The F-18-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 F-18-fluoro-PEG-triazoles-RGD(2) (F-18-FPTARGD2) 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 F-18-FPTA-RGD2 was synthesized with high radiochernical 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 F-18 labeling method based on click reaction may also be useful for radiolabeling of other biomolecules with azide groups in high yield.