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.
Highlights
Recent developments in bioorthogonal coupling chemistry offer a new way to create nuclear molecular imaging and therapy agents by allowing the targeting vector and its radiolabelledPLOS ONE | DOI:10.1371/journal.pone.0167425 December 9, 2016A 99mTc-Labelled Tetrazine for Bioorthogonal ChemistryResearch (CIHR) [www.cihr-irsc.gc.ca] grant #493840-16 held by JFV
High resolution mass spectra (HRMS) were obtained on a Waters QToF Ultima Global spectrometer. 99m-Pertechnetate [99mTcO4]- was obtained in saline solution from a 99Mo/99mTc generator supplied by Lantheus Medical Imaging
The target ligand was prepared by coupling the commercial tetrazine with the Boc-protected hydrazinonicotonic acid (HYNIC) precursor 1 [17] in the presence of pyBOP in DMF
Summary
Recent developments in bioorthogonal coupling chemistry offer a new way to create nuclear molecular imaging and therapy agents by allowing the targeting vector and its radiolabelledPLOS ONE | DOI:10.1371/journal.pone.0167425 December 9, 2016A 99mTc-Labelled Tetrazine for Bioorthogonal ChemistryResearch (CIHR) [www.cihr-irsc.gc.ca] grant #493840-16 held by JFV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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