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Radiosynthesis and Bioimaging of Antibacterial Agents

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dc.contributor.advisor Tonge, Peter J en_US
dc.contributor.author Liu, Li en_US
dc.contributor.other Department of Chemistry en_US
dc.date.accessioned 2013-05-22T17:35:07Z
dc.date.accessioned 2015-04-24T14:47:02Z
dc.date.available 2013-05-22T17:35:07Z
dc.date.available 2015-04-24T14:47:02Z
dc.date.issued 2012-08-01
dc.identifier Liu_grad.sunysb_0771E_11117 en_US
dc.identifier.uri http://hdl.handle.net/1951/59765 en_US
dc.identifier.uri http://hdl.handle.net/11401/71323 en_US
dc.description 186 pg. en_US
dc.description.abstract The dose and duration of treatment of antibacterial agents is normally established using plasma pharmacokinetic (PK) data together with information on drug efficacy once treatment has been initiated. Although plasma drug concentration is an important guide for establishing treatment protocols, recent studies indicate that the distribution of antibiotics in tissues is a more critical determinant and predictive factor for their activity. This is because most drugs exert their bactericidal effects at the site of infection rather than in the plasma, and because drug equilibration between plasma and infection site cannot always be achieved Therefore the tissue distribution of front-line TB drugs, including rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA), and enoyl-ACP reductase (FabI) inhibitors, PT-70 and PT-119, have been studied in healthy animals using PET and radiolabeled drugs. We find that their accumulations are consistent with the mechanism of excretion of each drug. In addition, we also find that the ability of the drugs to penetrate the blood-brain barrier decreases in the order PZA > INH > RIF. Estimated concentrations of RIF, INH and PZA in the lungs are at least 10, 10 and 1-3 times higher, respectively, than the minimum inhibitory concentration (MIC) values for these drugs against Mycobacterium tuberculosis (Mtb). Estimates of drug concentrations in the brain suggest that the concentrations of RIF and INH are 3-4 and >10 times higher than their MIC values, while the concentration of PZA is similar to or slightly higher than its MIC values. It is also estimated that the ability of PT-70 and their radiolabeled metabolites to penetrate the blood-brain barrier is similar to INH, while the ability of PT-119 is two times higher than INH. In addition, estimated AUC0-90min/MIC values for PT-70 and PT-119 are 38% and 37% of the INH AUC0-90min/MIC, respectively, which suggests that PT-70 and PT-119 have similar potential to treat CNS TB in non-human primates and humans. For pulmonary TB infection, it is estimated that the AUC0-90min/MIC values for PT-70 and PT-119 are 51% and 14%, respectively, of the INH AUC0-90min/MIC, which suggests that PT-70 is a better candidate than PT-119. For S. aureus infection, PT-119 demonstrates 10 times higher AUC0-90min/MIC value than that for PT-70 in the brain, and it is clear that PT-119 is a superior candidate for the treatment of S. aureus meningitis, although both AUC0-90min/MIC values are higher than calculated CSF AUC0-90min/MIC of a commonly prescribed antibiotic, Vancomycin.. The estimated concentrations in heart and kidney are at least 20 times higher for PT-70 and 100 times higher for PT-119 than the MIC values against S. aureus. The AUC0-90min/MIC for PT-119 is 16368 min and 51023 min for heart and kidney respectively, and both are ~3 times higher than the values for PT-70. The result suggested PT-119 is better candidate than PT-70 to treatment S. aureus infection in the heart and kidney. Finally, studies of radiolabeled antibacterial agents have been extended to Mtb and S. aureus infected animals to evaluate their abilities to localize bacteria. 2-[18F]F-INH has been imaged in Mtb infected mice in comparison with uninfected mice, and we have observed minor amplitude of signal (1:6:1 = infected : uninfected) at 1 hr post injection, although it may be partially contributing to a nonspecific inflammatory effect. [18F]FDG has been utilized to image S. aureus infection in systemic infected mice, and a 2.5:1 signal has been observed within spleen, which is consistent with highest level of bacteria population. These studies will help us to validate novel diagnostics for infectious disease 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 Antibacterial Agents, Diagnosis, Infectious Disease, Radiosynthesis, Tissue PK en_US
dc.title Radiosynthesis and Bioimaging of Antibacterial Agents en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Fowler, Joanna S en_US
dc.contributor.committeemember Ojima, Iwao en_US
dc.contributor.committeemember Schlyer, David J. en_US

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