{"doi":"10.17615/g90d-aw83","title":"Improved Metabolic Stability for 18 F PET Probes Rapidly Constructed via Tetrazine trans -Cyclooctene Ligation","abstract":"The fast kinetics and bioorthogonal nature of the tetrazine trans-cyclooctene (TCO) ligation makes it a unique tool for PET probe construction. In this study, we report the development of an 18F-labeling system based on a CF3-substituted diphenyl-s-tetrazine derivative with the aim of maintaining high reactivity while increasing in vivo stability. c(RGDyK) was tagged by a CF3-substituted diphenyl-s-tetrazine derivative via EDC-mediated coupling. The resulting tetrazine-RGD conjugate was combined with a 19F-labeled TCO derivative to give HPLC standards. The analogous 18F-labeled TCO derivative was combined with the diphenyl-s-tetrazine-RGD at μM concentration. The resulting tracer was subjected to in vivo metabolic stability assessment, and microPET studies in murine U87MG xenograft models. The diphenyl-s-tetrazine-RGD combines with an 18F-labeled TCO in high yields (>97% decay-corrected on the basis of TCO) using only 4 equiv of tetrazine-RGD relative to the 18F-labeled TCO (concentration calculated based on product’s specific activity). The radiochemical purity of the 18F-RGD peptides was >95% and the specific activity was 111 GBq/μmol. Noninvasive microPET experiments demonstrated that 18F-RGD had integrin-specific tumor uptake in subcutaneous U87MG glioma. In vivo metabolic stability of 18F-RGD in blood, urine and major organs showed two major peaks: one corresponded to the Diels-Alder conjugate and the other was identified as the aromatized analog. A CF3-substituted diphenyl-s-tetrazine displays excellent speed and efficiency in 18F-PET probe construction, providing nearly quantitative 18F labeling within minutes at low micromolar concentrations. The resulting conjugates display improved in vivo metabolic stability relative to our previously described system.","journal":"Figshare","year":2020,"id":113524,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"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":324007,"name":"Joseph M. Fox","orcid":"0000-0002-8258-1640","position":1,"is_corresponding":false},{"id":536074,"name":"Srinivasa R. Chintala","orcid":null,"position":2,"is_corresponding":false},{"id":290314,"name":"Peter S. Conti","orcid":null,"position":3,"is_corresponding":false},{"id":258567,"name":"Zibo Li","orcid":"0000-0002-1063-0298","position":4,"is_corresponding":false},{"id":291084,"name":"Hui Wang","orcid":"0000-0002-2346-8621","position":5,"is_corresponding":false},{"id":536075,"name":"Benjamin Giglio","orcid":null,"position":6,"is_corresponding":false},{"id":536076,"name":"Ramajeyam Selvaraj","orcid":null,"position":7,"is_corresponding":false},{"id":443863,"name":"Mengzhe Wang","orcid":"0000-0003-4654-6845","position":8,"is_corresponding":false},{"id":258566,"name":"Hong Yuan","orcid":"0000-0002-0535-3214","position":10,"is_corresponding":false},{"id":536073,"name":"Li Peng Yap","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:21.458038Z","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":[]}