engleski

Development of Non-Natural Nucleoside Analogues for Monitoring Gene Therapy with Positron Emission Tomography (PET)

Positron emission tomography (PET) has become a powerful scientific and clinical tool for probing biochemical processes in the human body. The clinical application of PET using molecules labelled with positron emitting radioisotopes has proven to be vital in the evaluation and diagnosis of diseases such as tumors, neurological disorders, cardiac diseases. Some purine and pyrimidine nucleoside analogues labelled with radionuclides 18F and 124I were evaluated for monitoring clinical gene therapy using PET. In order to develop new PET-tracers with greater sensitivity, specificity and low bystander cytotoxic effects, a new series of C-6 alkylated pyrimidines have been synthesized. Newly prepared compounds exhibited no toxicity and showed better in vitro binding affinities for herpes simplex virus type 1 thymidine kinase (HSV 1-TK) than prodrugs acyclovir and ganciclovir. Compounds that are phosphorylated by HSV 1-TK to their corresponding monophosphates and metabolically trapped in transfected cells represent new candidates for in vivo imaging of HSV 1-TK enzyme activity. The crystal structure of C-6 substituted pyrimidines in complex with HSV 1-TK have been solved. The syntheses and biological evaluations of unlabelled non-natural nucleoside analogues, as well as their 18F radiolabelling using nucleophilic substitution reaction on appropriate leaving groups will be presented.

C-6 Substituted Thymine Derivatives; 18F-Radiolabeling; Positron Emission Tomography

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