Type
Text
Type
Dissertation
Advisor
Tonge, Peter J | Jonhson, Francis | Carrico, Isaac | Smith-Jones, Peter.
Date
2015-05-01
Keywords
Chemistry | infectious diseases, PET imaging, PK/PD, radiosynthesis
Department
Department of Chemistry.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77078
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Target tissue pharmacokinetics (PK) is the link between plasma PK and pharmacodynamic (PD) effects. Tissue PK can be determined noninvasively using positron emission tomography (PET), which images molecules labelled with positron emitting isotopes and is an important tool for studying drug action in animals and humans. In applying this technology to infectious diseases, we have synthesized several antibacterial agents and determined their biodistribution in models of Staphylococcus aureus and Mycobacterium tuberculosis infection. Not only do these studies inform PK-PD relationships, but they also serve as the first steps in developing novel tracers for imaging bacterial infection in vivo. PT119 is a potent long residence time inhibitor of the Staphylococcus aureus enoyl-ACP reductase with antibacterial activity (PD) in two S. aureus infection models. To correlate the observed PD with plasma PK, PT119 was radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using PET. The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ∼1 h of analysis permitted by the carbon-11 half life. These data suggest that the in vivo efficacy of PT119 is not due to accumulation of the drug at the site of infection and supports the importance of drug-target residence time in this system. Pyrazinamide (PZA) is a first-line tuberculosis drug whose mechanism of action still remains to be fully elucidated. To explore the biodistribution of this important drug, PZA was labeled with fluorine-18 and 5-[18F]fluoropyrazinamide (5-[18F]PZA) was imaged in M. tuberculosis infected mice using PET. The imaging was rapid, noninvasive, and simultaneously allowed multiple tissues to be visualized simultaneously. Compared to uninfected animals, M. tuberculosis-infected mice had a higher PET signals within the lungs (ratio: 1.6:1). The results indicate that the accumulation of the probe in infected lungs, due to pathogen-specific metabolism, contributes to the in vivo efficacy of PZA, and suggests that 5-[18F]PZA may be able to monitor pathogen burden in infected patients. Furthermore, para-amino benzoic acid (PABA) from tetrahydrofolate (THF) biosynthesis pathway has been proposed as a promising candidate to detect bacterial infection in vivo, due to its ability to accumulate selectively in bacterial cells over mammalian cells. A three-step radiolabelling strategy for 2-[18F]PABA has been successfully developed. | Target tissue pharmacokinetics (PK) is the link between plasma PK and pharmacodynamic (PD) effects. Tissue PK can be determined noninvasively using positron emission tomography (PET), which images molecules labelled with positron emitting isotopes and is an important tool for studying drug action in animals and humans. In applying this technology to infectious diseases, we have synthesized several antibacterial agents and determined their biodistribution in models of Staphylococcus aureus and Mycobacterium tuberculosis infection. Not only do these studies inform PK-PD relationships, but they also serve as the first steps in developing novel tracers for imaging bacterial infection in vivo. PT119 is a potent long residence time inhibitor of the Staphylococcus aureus enoyl-ACP reductase with antibacterial activity (PD) in two S. aureus infection models. To correlate the observed PD with plasma PK, PT119 was radiolabeled with carbon-11 to evaluate its biodistribution and PK in both healthy and S. aureus infected mice using PET. The biodistribution of [11C]PT119 and/or its labeled metabolites did not differ significantly between the healthy group and the infected group, and PT119 was found to distribute equally between serum and tissue during the ∼1 h of analysis permitted by the carbon-11 half life. These data suggest that the in vivo efficacy of PT119 is not due to accumulation of the drug at the site of infection and supports the importance of drug-target residence time in this system. Pyrazinamide (PZA) is a first-line tuberculosis drug whose mechanism of action still remains to be fully elucidated. To explore the biodistribution of this important drug, PZA was labeled with fluorine-18 and 5-[18F]fluoropyrazinamide (5-[18F]PZA) was imaged in M. tuberculosis infected mice using PET. The imaging was rapid, noninvasive, and simultaneously allowed multiple tissues to be visualized simultaneously. Compared to uninfected animals, M. tuberculosis-infected mice had a higher PET signals within the lungs (ratio: 1.6:1). The results indicate that the accumulation of the probe in infected lungs, due to pathogen-specific metabolism, contributes to the in vivo efficacy of PZA, and suggests that 5-[18F]PZA may be able to monitor pathogen burden in infected patients. Furthermore, para-amino benzoic acid (PABA) from tetrahydrofolate (THF) biosynthesis pathway has been proposed as a promising candidate to detect bacterial infection in vivo, due to its ability to accumulate selectively in bacterial cells over mammalian cells. A three-step radiolabelling strategy for 2-[18F]PABA has been successfully developed. | 183 pages
Recommended Citation
Wang, Hui, "Radiolabelling and Pharmacokinetics of Antibacterial Agents Using Positron Emission Tomography" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2915.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2915