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Transforming thymidine into a magnetic resonance imaging probe for monitoring gene expression.


ABSTRACT: Synthetic chemistry has revolutionized the understanding of many biological systems. Small compounds that act as agonists and antagonists of proteins, and occasionally as imaging probes, have contributed tremendously to the elucidation of many biological pathways. Nevertheless, the function of thousands of proteins is still elusive, and designing new imaging probes remains a challenge. Through screening and characterization, we identified a thymidine analogue as a probe for imaging the expression of herpes simplex virus type-1 thymidine kinase (HSV1-TK). To detect the probe, we used chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI), in which a dynamic exchange process between an exchangeable proton and the surrounding water protons is used to amplify the desired contrast. Initially, five pyrimidine-based molecules were recognized as putative imaging agents, since their exchangeable imino protons resonate at 5-6 ppm from the water proton frequency and their detection is therefore less affected by endogenous CEST contrast or confounded by direct water saturation. Increasing the pK(a) value of the imino proton by reduction of its 5,6-double bond results in a significant reduction of the exchange rate (k(ex)) between this proton and the water protons. This reduced k(ex) of the dihydropyrimidine nucleosides fulfills the "slow to intermediate regime" condition for generating high CEST-MRI contrast. Consequently, we identified 5-methyl-5,6-dihydrothymidine as the optimal probe and demonstrated its feasibility for in vivo imaging of HSV1-TK. In light of these findings, this new approach can be generalized for designing specific probes for the in vivo imaging of a variety of proteins and enzymes.

SUBMITTER: Bar-Shir A 

PROVIDER: S-EPMC3560322 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Transforming thymidine into a magnetic resonance imaging probe for monitoring gene expression.

Bar-Shir Amnon A   Liu Guanshu G   Liang Yajie Y   Yadav Nirbhay N NN   McMahon Michael T MT   Walczak Piotr P   Nimmagadda Sridhar S   Pomper Martin G MG   Tallman Keri A KA   Greenberg Marc M MM   van Zijl Peter C M PC   Bulte Jeff W M JW   Gilad Assaf A AA  

Journal of the American Chemical Society 20130116 4


Synthetic chemistry has revolutionized the understanding of many biological systems. Small compounds that act as agonists and antagonists of proteins, and occasionally as imaging probes, have contributed tremendously to the elucidation of many biological pathways. Nevertheless, the function of thousands of proteins is still elusive, and designing new imaging probes remains a challenge. Through screening and characterization, we identified a thymidine analogue as a probe for imaging the expressio  ...[more]

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