67Ga-labeled deferoxamine derivatives for imaging bacterial infection: Preparation and screening of functionalized siderophore complexes.

INTRODUCTION: Deferoxamine (DFO) is a siderophore that bacteria use to scavenge iron and could serve as a targeting vector to image bacterial infection where current techniques have critical limitations. [67Ga]-DFO, which is a mimetic of the corresponding iron complex, is taken up by bacteria in culture, however in vivo it clears too rapidly to allow for imaging of infection. In response, we developed several new DFO derivatives to identify those that accumulate in bacteria, and at sites of infection, and that could potentially have improved pharmacokinetics. METHODS: A library of DFO derivatives was synthesized by functionalizing the terminal amine group of DFO using three different carbamate-forming reactions. Uptake of [67Ga]-DFO and the 67Ga-labeled derivatives by bacteria and the biodistribution of lead compounds were studied. RESULTS: 67Ga-labeled DFO derivatives were prepared and isolated in >90% radiochemical yield and >95% radiochemical purity. The derivatives had significant but slower uptake rates in Staphylococcus aureus than [67Ga]-DFO (6% to 60% of the control rate), with no uptake for the most lipophilic derivatives. Biodistribution studies in mice with a S. aureus infection in one thigh revealed that the ethyl carbamate derivative had an excellent infected-to-non-infected ratio (11:1), but high non-specific localization in the gall bladder, liver and small intestine. CONCLUSIONS: The work reported shows that it is possible to functionalize DFO-type siderophores and retain active uptake of the 67Ga-labeled complexes by bacteria. Novel 67Ga-labeled DFO derivatives were specifically taken up by S. aureus and selected derivatives demonstrated in vivo localization at sites of infection. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: 67Ga-labeled DFO derivatives were actively transported by bacteria using the iron-siderophore pathway, suggesting that it is possible to develop siderophore-based radiopharmaceuticals for imaging bacterial infection.

Correction: A 99mTc-Labelled Tetrazine for Bioorthogonal Chemistry. Synthesis and Biodistribution Studies with Small Molecule trans-Cyclooctene Derivatives.

[This corrects the article DOI: 10.1371/journal.pone.0167425.].

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

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.