Seminar

Seminar

Evaluation of Trehalose Derivatives as Radiotracers Specific for Tuberculosis in Animal Models of Disease

  • POSTED DATE : 2016-03-21
  • WRITER : 관리자
  • HIT : 3153
  • DATE : 2016-03-28
  • PLACE : 화학관 330118호

제  목 : Evaluation of Trehalose Derivatives as Radiotracers Specific for Tuberculosis in Animal Models of Disease


연  사 : 이승서 교수님(University of Southampton)


Evaluation of Trehalose Derivatives as Radiotracers Specific for Tuberculosis in Animal Models of Disease


 


We are developing PET radiotracers specific to Mycobacterium tuberculosis (Mtb). In evaluating new treatments, [18F]-2-fluoro-2-deoxyglucose (FDG) has been shown to be a useful tool, but it is not highly correlated with bacterial burden. We are evaluating trehalose radiotracers which may be covalently incorporated in vivo into the Mtb cell wall to give a PET signal directly correlated to bacterial burden rather than reporting on inflammation or other host response.


We have designed several [18F]-labeled trehalose derivatives and are evaluating them in animal models of tuberculosis. Two of the probes, [18F]-6-fluoro-6-deoxytrehalose (6-FTre) and [18F]-epi-4-fluoro-4-deoxytrehalose (epi-4-FTre) are chemically synthesized in a method similar to [18F]-2-fluoro-2-deoxyglucose (FDG) from peracetylated precursors, and one probe, [18F]-2-fluoro-2-deoxytrehalose (2-FTre), is chemoenzymatically synthesized in a one-pot, three-enzyme cocktail from [18F]-FDG. All three were initially evaluated in Mtb-infected rabbits by acquiring PET/CT scans and blood and urine samples for metabolism analysis. The 2-FTre probe is also currently being evaluated in a non-human primate model of tuberculosis.


In initial experiments in Mtb-infected rabbits, the 6-FTre probe was rapidly metabolized to [18F]-6-fluoro- 6-deoxyglucose. However, the epi-4-FTre was metabolically stable and did label lesions in the rabbit lung. A typical signal-to-noise for labeling was 2-3:1. The 2-FTre gave a slightly higher signal-to-noise and also appeared to give some differential labeling when compared to FDG. However, we saw potential probe metabolism and decided to change to a marmoset model of tuberculosis, which should express lower levels of trehalase than rabbits. The 2-FTre is currently under evaluation in a marmoset model of disease and appears to be labeling lesions selectively. No metabolism is observed in blood or urine of the marmosets.


The trehalose derived probes are demonstrating uptake in PET scans at the site of Mtb lesions. This technology will allow us to selectively label Mtb infection and monitor treatment in animals on experimental drug regimens.