Deep-seated bacterial infections caused by pathogens such as Staphylococcus aureus are difficult to manage clinically partly due to the lack of non-invasive, sensitive and specific diagnostic tool for an early and accurate diagnosis. While traditional imaging techniques such as computed tomography, X-ray and magnetic resonance imaging can non-invasively identify anatomical changes associated with infection, they cannot detect early-stage bacterial infections or distinguish bacterial infection from other diseases. This problem can be potentially addressed by molecular imaging such as positron emission tomography (PET) with the development of novel infection-specific radiotracers.
The development of a first-generation bacteria-specific radiotracer, 2-[18F]F-p-aminobenzoic acid (2-[18F]F-PABA) will be described. Experimental findings showed that 2-[18F]F-PABA could non-invasively identify, localize and monitor S. aureus infection with excellent sensitivity and specificity in a rodent soft tissue infection model. However, it was observed that 2-[18F]F-PABA is rapidly N-acetylated and eliminated leading to low absolute uptake at the infection site.
To address the metabolic liabilities associated with 2-[18F]F-PABA, a pro-drug strategy was used to develop a second-generation radiotracer, 2-[18F]F-ENB, in which the acid was protected with an ester and the amine was replaced with a nitro group. PET/CT imaging of 2-[18F]F-ENB and its corresponding acid metabolite, 2-[18F]F-NB, in a rat soft tissue infection model demonstrated that the tracers could differentiate S. aureus infection from sterile inflammation with a tissue contrast ratio of 17-fold compared to the 8-fold difference observed for 2-[18F]F-PABA. Mode of action studies at the biochemical and the cellular level support a mechanism of accumulation of the radiotracers by S. aureus via their incorporation into the folic acid. The potential of the second-generation radiotracer for detecting deep-seated infections was evaluated in a rat model of infective endocarditis and a mouse prosthetic joint infection model. Preliminary data suggest that 2-[18F]F-ENB PET imaging can localize cardiac infection.
In addition to imaging infection, the PET studies were also extended to the development of novel radiotracers based on inhibitors of Bruton’s tyrosine kinase (Btk). Btk is a non-receptor tyrosine kinase involved in autoimmune diseases and B cell malignancies, and the long term goal of this project is to non-invasively quantify the target occupancy of Btk inhibitors in vivo with PET imaging. Novel 18F PET ligands were designed and synthesized based on the Btk inhibitor CC-292, and then evaluated in a Ramos cell mice xenograft model using PET imaging. The biodistribution and the potential of these tracers as Btk-specific in vivo labeling agents were examined.
In a separate project, the development of new antibacterial agents with novel mechanisms of action (MOA) was also pursued. Compounds based on the oxaborole chemical scaffold were proposed to have distinct MOA against two validated antibacterial targets: DNA ligase LigA and leucyl-tRNA synthetase (LeuRS). A series of compounds were synthesized and evaluated at the biochemical and the whole-cell level. The structure-activity relationship (SAR) of these compounds is discussed.
|Advisor:||Tonge, Peter J.|
|Commitee:||Ngai, Ming-Yu, Boros, Eszter, Turkman, Nashaat|
|School:||State University of New York at Stony Brook|
|School Location:||United States -- New York|
|Source:||DAI-B 82/3(E), Dissertation Abstracts International|
|Subjects:||Chemistry, Medical imaging, Microbiology|
|Keywords:||Bacterial infection, Novel antibacterial agents, PET radiotracers|
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