A Tc-99m-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives

作者：Vito Alyssa; Alarabi Hussain; Czorny Shannon; Beiraghi Omid; Kent Jeff; Janzen Nancy; Genady Afaf R; Alkarmi Salma A; Rathmann Stephanie; Naperstkow Zoya; Blacker Megan; Llano Lisset; Berti Paul J; Valliant John F^*

来源：PLos One, 2016, 11(12): e0167425.

DOI：10.1371/journal.pone.0167425

A convenient strategy to radiolabel a hydrazinonicotonic acid (HYNIC)-derived tetrazine with Tc-99m was developed, and its utility for creating probes to image bone metabolism and bacterial infection using both active and pretargeting strategies was demonstrated. The Tc-99m-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 Tc-99m-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 Tc-99m-HYNIC-tetrazine before injection and this active targeting also showed high specific uptake in the knees and shoulders, whereas control Tc-99m-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 Tc-99m-HYNIC-tetrazine for preparing new technetium radiopharmaceuticals, including those based on small molecule targeting constructs containing TCO, using either active or pretargeting strategies.

• 出版日期2016-12-9