Tetrazine Glycoconjugate for Pretargeted Positron Emission Tomography Imaging of trans -Cyclooctene-Functionalized Molecular Spherical Nucleic Acids

• Published in: ACS omega Vol. 8; no. 48; pp. 45326 - 45336
• Main Authors: Auchynnikava, Tatsiana, Äärelä, Antti, Liljenbäck, Heidi, Järvinen, Juulia, Andriana, Putri, Kovacs, Luciana, Rautio, Jarkko, Rajander, Johan, Virta, Pasi, Roivainen, Anne, Li, Xiang-Guo, Airaksinen, Anu J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 05.12.2023
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.3c04041

Pretargeted concept in positron emission tomography (PET) together with bioorthogonal chemistry is an elegant solution to study processes with slow pharmacokinetics by utilizing radiotracers labeled with short-lived radionuclides. Namely, radiotracers based on tetrazine ligation with -cyclooctene (TCO) via the inverse electron demand Diels-Alder (IEDDA) reaction have become a state-of-the-art for the pretargeted PET imaging. For radiolabeling of tetrazine scaffolds, indirect radiofluorination methods are often preferred, as tetrazines are vulnerable to harsh conditions typically necessary for the direct radiofluorination. F-Fluoroglycosylation is an indirect radiofluorination method, which allows the introduction of a widely accessible glucose analog 2-[ F]fluoro-2-deoxy-d-glucose ([ F]FDG) to aminooxy-functionalized precursors via oxime formation. Here, we report the biological evaluation of [ F]FDG-Tz as a tracer for pretargeted PET imaging of TCO-functionalized molecular spherical nucleic acids (MSNA) against human epidermal growth factor receptor 2 (HER2) mRNA. The oxime ether formation between [ F]FDG and tetrazine oxyamine resulted in [ F]FDG-Tz with high radiochemical purity (>99%) and moderate yields (6.5 ± 3.6%, = 5). Biological evaluation of [ F]FDG-Tz in healthy mice indicated favorable pharmacokinetics with quick blood clearance, urinary excretion as the main elimination route, and the absence of GLUT1 transportation. The successful pretargeted experiments with TCO-functionalized MSNA revealed higher tumor uptake compared to preclicked MSNA in HER2-expressing human breast cancer xenograft-bearing mice.