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

Amnon Bar-Shir, Guanshu Liu, Yajie Liang, Nirbhay N. Yadav, Michael T. McMahon, Piotr Walczak, Sridhar Nimmagadda, Martin G. Pomper, Keri A. Tallman, Marc M. Greenberg, Peter C.M. Van Zijl, Jeff W.M. Bulte, Assaf A. Gilad

Research output: Contribution to journalArticlepeer-review

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 pKa value of the imino proton by reduction of its 5,6-double bond results in a significant reduction of the exchange rate (kex) between this proton and the water protons. This reduced kex 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.

Original languageEnglish (US)
Pages (from-to)1617-1624
Number of pages8
JournalJournal of the American Chemical Society
Volume135
Issue number4
DOIs
StatePublished - Jan 30 2013

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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