title: Preparation and Evaluation of 99mTc-labeled Tridentate Chelates for Pre-targeting Using Bioorthogonal Chemistry.
abstract: Pre-targeting combined with bioorthogonal chemistry is emerging as an effective way to create new radiopharmaceuticals. Of the methods available, the inverse electron demand Diels-Alder (IEDDA) cycloaddition between a radiolabeled tetrazines and trans-cyclooctene (TCO) linked to a biomolecule has proven to be a highly effective bioorthogonal approach to imaging specific biological targets. Despite the fact that technetium-99m remains the most widely used isotope in diagnostic nuclear medicine, there is a scarcity of methods for preparing99mTc-labeled tetrazines. Herein we report the preparation of a family of tridentate-chelate-tetrazine derivatives and their Tc(I) complexes. These hitherto unknown compounds were radiolabeled with99mTc using a microwave-assisted method in 31% to 83% radiochemical yield. The products are stable in saline and PBS and react rapidly with TCO derivatives in vitro. Their in vivo pre-targeting abilities were demonstrated using a TCO-bisphosphonate (TCO-BP) derivative that localizes to regions of active bone metabolism or injury. In murine studies, the99mTc-tetrazines showed high activity concentrations in knees and shoulder joints, which was not observed when experiments were performed in the absence of TCO-BP. The overall uptake in non-target organs and pharmacokinetics varied greatly depending on the nature of the linker and polarity of the chelate.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Bilton
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Ahmad
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University.
authors.forename: Nancy
authors.initials: N
authors.lastname: Janzen
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University.
authors.forename: Shannon
authors.initials: S
authors.lastname: Czorny
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University; valliant@mcmaster.ca.
authors.forename: John F
authors.initials: JF
authors.lastname: Valliant
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology*; D061565:Cycloaddition Reaction; D034242:Cyclooctanes / Q000737:chemistry*; D004164:Diphosphonates / Q000032:analysis; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D019275:Radiopharmaceuticals / Q000737:chemistry; D013667:Technetium / Q000494:pharmacology*
chemical_list: D002614:Chelating Agents; D034242:Cyclooctanes; D004164:Diphosphonates; D019275:Radiopharmaceuticals; D013667:Technetium