title: A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives.
abstract: A convenient strategy to radiolabel a hydrazinonicotonic acid (HYNIC)-derived tetrazine with 99mTc was developed, and its utility for creating probes to image bone metabolism and bacterial infection using both active and pretargeting strategies was demonstrated. The 99mTc-labelled HYNIC-tetrazine was synthesized in 75% yield and exhibited high stability in vitro and in vivo. A trans-cyclooctene (TCO)-labelled bisphosphonate (TCO-BP) that binds to regions of active calcium metabolism was used to evaluate the utility of the labelled tetrazine for bioorthogonal chemistry. The pretargeting approach, with 99mTc-HYNIC-tetrazine administered to mice one hour after TCO-BP, showed significant uptake of radioactivity in regions of active bone metabolism (knees and shoulders) at 6 hours post-injection. For comparison, TCO-BP was reacted with 99mTc-HYNIC-tetrazine before injection and this active targeting also showed high specific uptake in the knees and shoulders, whereas control 99mTc-HYNIC-tetrazine alone did not. A TCO-vancomycin derivative was similarly employed for targeting Staphylococcus aureus infection in vitro and in vivo. Pretargeting and active targeting strategies showed 2.5- and 3-fold uptake, respectively, at the sites of a calf-muscle infection in a murine model, compared to the contralateral control muscle. These results demonstrate the utility of the 99mTc-HYNIC-tetrazine for preparing new technetium radiopharmaceuticals, including those based on small molecule targeting constructs containing TCO, using either active or pretargeting strategies.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Vito
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Hussain
authors.initials: H
authors.lastname: Alarabi
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Shannon
authors.initials: S
authors.lastname: Czorny
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Omid
authors.initials: O
authors.lastname: Beiraghi
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jeff
authors.initials: J
authors.lastname: Kent
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Janzen
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.|Department of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt.
authors.forename: Afaf R
authors.initials: AR
authors.lastname: Genady
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Salma A
authors.initials: SA
authors.lastname: Al-Karmi
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rathmann
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Naperstkow
authors.affiliation: Centre for Probe Development and Commercialization, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Megan
authors.initials: M
authors.lastname: Blacker
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Lisset
authors.initials: L
authors.lastname: Llano
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.|Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Berti
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.|Centre for Probe Development and Commercialization, McMaster University, Hamilton, Ontario, Canada.
authors.forename: John F
authors.identifier: 0000-0002-1461-552X
authors.initials: JF
authors.lastname: Valliant
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging*; D034242:Cyclooctanes / Q000737:chemistry / Q000493:pharmacokinetics*; D004164:Diphosphonates / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics*; D006834:Hydrazines / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D009539:Nicotinic Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging / Q000379:methods; D013203:Staphylococcal Infections / Q000000981:diagnostic imaging*; D013211:Staphylococcus aureus / Q000302:isolation & purification; D013667:Technetium / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014640:Vancomycin / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: C120392:6-hydrazinopyridine-3-carboxylic acid; D034242:Cyclooctanes; D004164:Diphosphonates; D006573:Heterocyclic Compounds, 1-Ring; D006834:Hydrazines; D009539:Nicotinic Acids; D014640:Vancomycin; D013667:Technetium