18F PET has a number of attributes that make it clinically attractive, including almost 100% positron efficiency, very high specific radioactivity, and short half-life of ∼110 min. However, the short half-life of 18F and the poor nucleophilicity of fluoride make it difficult to incorporate 18F in complex molecules. Recently, the tetrazine-trans-cyclooctene ligation has been introduced as a novel 18F labeling method that proceeds with fast reaction rates without any catalysis. To further explore the scope of this reaction, herein we reported an efficient method for 18F-lableing of free cysteine-containing bioligands based on the tetrazine-trans-cyclooctene ligation. The newly developed method was tested for site specific labeling of both c(RGDyC) and VEGF-SH protein. Starting with 4 mCi of 18F-trans-cyclooctene and only 10 μg of tetrazine-RGD (80-100 µM) or 15 μg of tetrazine-VEGF (6.0 µM), the 18F labeled RGD peptide or VEGF protein could be obtained in 95% yield and 75% yield within five minutes. The obtained tracers were then evaluated in small animals. In conclusion, a highly efficient method has been developed for site-specific 18F labeling of cysteine containing peptides and proteins. The special characteristics of the tetrazine-trans-cyclooctene ligation provide unprecedented opportunities to synthesize 18F-labeled probes with high specific activity for PET applications.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 370. doi:1538-7445.AM2012-370