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Radiolabelling and Pharmacokinetics of Antibacterial Agents Using Positron Emission Tomography

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dc.contributor.advisor Tonge, Peter J en_US
dc.contributor.author Wang, Hui en_US
dc.contributor.other Department of Chemistry en_US
dc.date.accessioned 2017-09-20T16:51:52Z
dc.date.available 2017-09-20T16:51:52Z
dc.date.issued 2015-05-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/77078 en_US
dc.description 183 pgs en_US
dc.description.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. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Chemistry en_US
dc.subject.other infectious diseases, PET imaging, PK/PD, radiosynthesis en_US
dc.title Radiolabelling and Pharmacokinetics of Antibacterial Agents Using Positron Emission Tomography en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Jonhson, Francis en_US
dc.contributor.committeemember Carrico, Isaac en_US
dc.contributor.committeemember Smith-Jones, Peter en_US

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