{"doi":"10.17615/bwht-9643","title":"Conformationally Strained trans- Cyclooctene (sTCO) Enables the Rapid Construction of 18 F-PET Probes via Tetrazine Ligation","abstract":"The bioorthogonal reaction between tetrazines and trans-cyclooctenes is a method for the rapid construction of F-18 probes for PET imaging. Described here is a second generation 18F-labeling system based on a conformationally strained trans-cyclooctene (sTCO)—a dienophile that is approximately 2 orders of magnitude more reactive than conventional TCO dienophiles. Starting from a readily prepared tosylate precursor, an 18F labeled sTCO derivative (18F-sTCO) could be synthesized in 29.3 +/- 5.1% isolated yield and with high specific activity. Tetrazine ligation was carried out with a cyclic RGD-conjugate of a diphenyl-s-tetrazine analogue (RGD-Tz) chosen from a diene class with an excellent combination of fast reactivity and stability both for the diene as well as the Diels-Alder adduct. For both the tetrazine and the sTCO, mini-PEG spacers were included to enhance solubility and improve the in vivo distribution profile of the resulting probe. Extremely fast reactivity (up to 2.86 x 105 M-1s-1 at 25 °C in water) has been observed in kinetic studies in the reaction of sTCO with diphenyl-s-tetrazine derivatives. A kinetic study on sTCO diastereomers in 55:45 MeOH:water showed that the syn-diastereomer displayed slightly faster reactivity than the anti-diastereomer. An 18F-sTCO conjugate with RGD-Tz demonstrated prominent and persistent tumor uptake in vivo with good tumor-to-background contrast. Unlike most radiolabeled RGD peptides, the tumor uptake of this PET agent increased from 5.3 +/- 0.2% ID/g at 1 h post injection (p.i.), to 8.9 +/- 0.5% ID/g at 4 h p.i., providing evidence for prolonged blood circulation. These findings suggest that tetrazine ligations employing 18F-sTCO should serve as a powerful and general platform for the rapid construction of peptide or protein derived PET agents.","journal":"UNC Libraries","year":2020,"id":111557,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":528962,"name":"Dennis Svatunek","orcid":"0000-0003-1101-2376","position":1,"is_corresponding":false},{"id":528963,"name":"Yuan Hong","orcid":"0009-0007-5585-6681","position":2,"is_corresponding":false},{"id":324007,"name":"Joseph M. Fox","orcid":"0000-0002-8258-1640","position":3,"is_corresponding":false},{"id":529799,"name":"Katarina Rohlfing","orcid":null,"position":4,"is_corresponding":false},{"id":529800,"name":"Zhanghong Wu","orcid":null,"position":5,"is_corresponding":false},{"id":258567,"name":"Zibo Li","orcid":"0000-0002-1063-0298","position":6,"is_corresponding":false},{"id":529801,"name":"Ben Giglio","orcid":null,"position":7,"is_corresponding":false},{"id":528964,"name":"Yu Liu","orcid":"0000-0003-2608-6941","position":8,"is_corresponding":false},{"id":291084,"name":"Hui Wang","orcid":"0000-0002-2346-8621","position":9,"is_corresponding":false},{"id":443863,"name":"Mengzhe Wang","orcid":"0000-0003-4654-6845","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:05.597252Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}