The noninvasive imaging of tissue oxygenation and acidity is of utmost importance in evaluating tumor progression, or ischemic injury, and selection of appropriate therapies. Cell metabolism depends on the oxygen supply, which in turn influences the extracellular pH, and transmembrane pH gradients. Electron Paramagnetic Resonance Imaging equipment, which is now commercially available for use in small animals, can provide specific information about pO2 or pH in 3D format without background interference, because paramagnetic probes that detect these parameters are exogenous to biological systems. In this project, a trityl radical probe named pHMT will be synthesized for use as dual pH-pO2 EPR Imaging probe in vivo. Trityl probes offer enormous advantages compared to the commercially available nitroxide probes in terms of stability, and EPR imaging resolution. Concurrent EPR imaging of pH and pO2 in vivo using dual-function trityl probes is highly desired, as it will provide direct evidence of the interplay between these two important biomarkers, but for the moment it is not possible in vivo. Based on our preliminary data on Finland trityl (FT) spin probes and derivatives, a systematic approach is proposed for the efficient synthesis, and chemical evaluation of a new, highly water soluble dual function pH-pO2 spin probe, pHMT. Our assessment formulated with data obtained from similar FT compounds is that pHMT is ideally suited for EPR imaging applications in vivo. The project will be divided in two parts: SA1: Synthesize pHMT, a dual function pH-pO2 sensitive EPR imaging probe based on hydroxymethyl trityl structure. SA2: Characterize via EPR spectroscopy and imaging the newly synthesized probes.
The synthesis of pHMT is proposed. It is a new water soluble probe, of dual pH-pO2 functionality, with maximal sensitivity for use in electron paramagnetic resonance (EPR) imaging in vivo. Accurate knowledge of hypoxia and acidity, both biomarkers of tissue heterogeneity, will impact the choice of therapeutic treatments.
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| Dhimitruka, Ilirian; Eubank, Timothy D; Gross, Amy C et al. (2015) New class of 8-aryl-7-deazaguanine cell permeable fluorescent probes. Bioorg Med Chem Lett 25:4593-6 |
| Bobko, Andrey A; Dhimitruka, Ilirian; Zweier, Jay L et al. (2014) Fourier transform EPR spectroscopy of trityl radicals for multifunctional assessment of chemical microenvironment. Angew Chem Int Ed Engl 53:2735-8 |
