Naslov
Non-natural nucleoside analogues for noninvasive monitoring of tumor cells using positron emission tomography (PET)

Autori
Raić-Malić, Silvana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Symposium on Nucleic Acid Chemistry, Structure and Interactions : Program and book of abstracts / Vodiškar, Mateja ; Plavec, Janez - Ljubljana : Slovenian NMR Cenre, National Institute of Chemistry, 2010, 31-31

ISBN
978-961-6104-16-6

Skup
Symposium on Nucleic Acid Chemistry, Structure and Interactions

Mjesto i datum
Ljubljana, Slovenija, 29.05.2010. - 31.05.2010

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Positron emission tomography (PET); Herpes virus type 1 thymidine kinase (HSV1-TK); C-6 alkylated pyrimidines; phosphorylation

Sažetak
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 labeled with positron emitting radioisotopes has proven to be vital in the evaluation and diagnosis of diseases such as tumors, neurological disorders, cardiac diseases. The most studied system for the visualization of gene expression in animals and humans is Herpes virus type 1 thymidine kinase (HSV1-TK). Compounds that are phosphorylated by HSV1-TK to their corresponding monophosphates and metabolically trapped in transfected cells represent new candidates for in vivo imaging of HSV1-TK enzyme activity. Some purine and pyrimidine nucleoside analogues labeled with radionuclide 18F and 124I were evaluated for monitoring clinical gene therapy using PET. A striking difference is that while all pyrimidine nucleoside analogues show low, if any, bystander killing effect, purine derivatives such as ganciclovir are endowed with bystander killer effect. Besides, most of the PET reporter probes including 18F-9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG), the most widely used reporter probe, are plagued with several shortcomings such as unfavorable pharmacokinetics and cytotoxicity. In the effort of further exploring the pyrimidine scaffold as putative starting point for development of novel PET tracers we have identified a new series of C-6 alkylated pyrimidines as HSV1-TK substrates. Newly prepared compounds exhibited no toxicity and showed better in vitro binding affinities for herpes simplex virus type 1 thymidine kinase (HSV1-TK) than prodrugs acyclovir and ganciclovir. The crystal structures of C-6 substituted pyrimidines in complex with HSV1-TK have been solved. The syntheses, biochemical and biological evaluations of unlabelled non-natural nucleoside analogues in vitro were performed. PET tracer candidates that are selectively and efficiently phosphorylated by thymidine kinase were labeled with radionuclide 18F using nucleophilic substitution reaction on appropriate leaving groups. The demonstration of monitoring efficiency of the best candidate in vivo using tumor-bearing mice will be also presented.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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