Radiosynthesis and Preclinical Evaluation of [99mTc]Tc-Tigecycline Radiopharmaceutical to Diagnose Bacterial Infections

Abstract

Background/objectives: As a primary source of mortality and disability, bacterial infections continue to develop a severe threat to humanity. Nuclear medicine imaging (NMI) is known for its promising potential to diagnose deep-seated bacterial infections. This work aims to develop a new technetium-99m (^99mTc) labeled tigecycline radiopharmaceutical as an infection imaging agent.

Methods: Reduced ^99mTc was used to make a coordinate complex with tigecycline at pH 7.7-7.9 at room temperature. Instantaneous thin-layer chromatography impregnated with silica gel (ITLC-SG) and ray detector equipped high-performance liquid chromatography (ray-HPLC) was performed to access the radiolabeling yield and radiochemical purity (RCP).

Results: More than 91% labeling efficiency was achieved after 25 min of mild shaking of the reaction mixture. The radiolabeled complex was found intact up to 4 h in saline. Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infection-induced rats were used to record the biodistribution of the radiopharmaceutical and its target specificity; 2 h' post-injection biodistribution revealed a 2.39 ± 0.29 target/non-target (T/NT) ratio in the E. coli infection-induced animal model, while a 2.9 ± 0.31 T/NT value was recorded in the S. aureus bacterial infection-induced animal model. [^99mTc]Tc-tigecycline scintigraphy was performed in healthy rabbits using a single photon emission computed tomography (SPECT) camera. Scintigrams showed normal kidney perfusion and excretion into the bladder.

Conclusion: In conclusion, the newly developed [^99mTc]Tc-tigecycline radiopharmaceutical could be considered to diagnose broad-spectrum bacterial infections.

Keywords: E. coli; S. aureus; SPECT imaging; antibiotics; infection; nuclear medicine; radioisotope; radiopharmaceuticals; tigecycline.

Figure 1

Chemical structure of tigecycline antibiotic.

Figure 2

Study of the effect of pH (a), ligand concentration (b), reducing agent (c), and reaction period (d). All values are represented as mean (n = 3) ± S.D.

Figure 3

ITLC-SG analysis description for the determination of [^99mTc]Tc-tigecycline, free ^99mTcO₄⁻, and hydrolyzed ^99mTc.

Figure 4

Ray-HPLC radio-chromatogram showing the peaks of [^99mTc]Tc-tigecycline and impurities.

Figure 5

In vitro stability of the radiochemical in saline. All values are represented as mean (n = 3) ± S.D.

Figure 6

Antibacterial activity of [^99mTc]Tc-tigecycline (A) and untagged tigecycline (B) against S. aureus and E. coli bacterial strains. All values are represented as mean (n = 3) ± S.D.

Figure 7

Distribution of ^99mTc labeled tigecycline in octanol and water.

Figure 8

Biodistribution in rats infected with (a) S. aureus bacterial strain, (b) with E. coli bacterial strain, and (c) turpentine oil (inflammation). All values are represented as mean (n = 3) ± S.D.

Figure 9

Scintigraphy scan of [^99mTc]Tc-tigecycline in normal rabbit at 0 h, 1 h, 2 h, and 4 h post injection period.