Development of tuberculosis imaging probes based on sugars and proteins

Tuberculosis (TB) is one of the oldest known human diseases, caused by Mycobacterium tuberculosis. The techniques currently employed for diagnosis are generally insensitive and non-specific. Positron emission tomography (PET) combined with computed tomography (CT) is used extensively in clinics and is among the advanced molecular imaging modalities for disease diagnosis and for monitoring the response to treatment. In this thesis we described new probes based on sugars and proteins. We used an optimised biocatalytic approach for the synthesis of 2-fluoro-2-deoxy-D-trehalose (FDT). We scaled up synthesis for pre-clinical studies giving strong consideration to the expression host for enzymes. The use of rare biocatalytic methods employed in the synthesis was unique for the development of a radioisotope probe. We then sought to develop an LC-MS based method for the detection of FDT in vitro and in vivo. Toxicity of the synthesised sugar compound was assessed in two different animal models. FDT administered to naïve marmosets labeled very little tissue in the lung, but when the animals were infected with M. tuberculosis, the tubercular lesions took up the radiolabelled FDT and [¹⁸F] FDT monomycolate was isolated ... (continues)