Whether you’re talking about MRI, which doctors use to image tissues in the body, or the brand of nuclear magnetic resonance spectroscopy used by organic chemists, Assistant Professor of Chemistry Christos Constantinides says the core idea behind the technique is basically the same. You start with a sample — in organic chemistry, it’s a compound you want to know the structure of, and in an MRI, it’s your body — and you surround it within a powerful magnet. The magnetic field causes the nuclei in the atoms in the sample, which have naturally occurring random spins, to momentarily align these spins with the external field, either in a parallel (lower energy state) or antiparallel orientation (higher energy state). Then, you shoot radio waves at the sample, which causes the spins of the parallel-spinning nuclei to momentarily flip to an antiparallel state. When you turn off the radio waves, these flipped nuclei then “relax,” returning to their original orientation. That releases a small amount of energy as an oscillating magnetic field, which induces an electrical signal. This signal is detected and processed to generate an NMR spectrum in the case of molecular analysis. For MRI, it can be used to create an image of tissues in the body.
Constantinides says NMR is an extremely powerful technique, but it still has some limitations. Notably, certain substances give off very weak signals when they relax out of their “excited” state, which means the spectra generated through NMR often don’t tell you everything you want to know. Scientists have discovered various ways to enhance NMR’s powers. For example, with MRI, contrast dyes can help doctors see more details in the brain, heart, blood vessels, soft tissues and tumors. In materials chemistry, Constantinides says organic chemists use what are called polarizing agents, which are chemical compounds that are added in solution with the sample. Chemically speaking, these compounds are “radicals,” meaning they have at least one unpaired electron (most atoms have electrons which orbit the nucleus in pairs). In an NMR environment, Constantinides says these unpaired electrons are able to influence the nucleus of the molecules in the sample through spin polarization transfer mechanisms, indirectly assisting the “flipping” process that is essential to NMR imaging. “This basically increases the sensitivity of the technique,” he says. “So for molecules that are difficult to get a good NMR spectrum because they give very weak signals, by adding a little bit of this organic radical substance, it basically amplifies the signal and you get more detail.”
Polarizing agents have greatly enhanced NMR spectroscopy, but they aren’t universally effective. For example, Constantinides says today’s most common polarizing agents, known as nitronyl nitroxides, can only be used with certain kinds of substances, because these radicals react with compounds that oxidize easily. With a and in conjunction with the Ames National Laboratory, Constantinides is looking to create novel polarizing agents that don’t have these limitations. He says when he describes this project to others, it ends up sounding like a lot of physics, because of the potential applications for NMR and MRI. But the day-to-day work will be a lot of advanced and, at times, unglamorous synthetic organic chemistry. During the three-year project, Constantinides estimates they’ll create 50 to 100 new derivatives of a class of molecules known as Blatter radicals — each of which takes weeks and a carefully planned sequence of chemical reactions to create. “Each compound requires six to 10 different steps,” he says. “One step can take multiple days to set up the chemical reaction, then you have to process it, clean it up a little bit and remove all the inorganic stuff, purify it, and then characterize it to see if you’ve made what you think you’ve made.” To assist with the labor-intensive research, Constantinides is hiring a postdoctoral research fellow and several undergraduates, which will give students an opportunity to get hands-on experience in some very advanced chemistry.
Even with this patient, methodical approach, Constantinides says success in organic chemistry is never assured. Over the years, he’s refined multiple techniques for creating certain kinds of molecules. But when you’re making something totally new, he says you never really know which methods will give you the best result — or whether your plan will even work — until you actually try it. “Maybe all of them fail, and then you have to try something totally different. It can be a lot of trial and error,” he says. As each new polarizing agent is created, Constantinides says they’ll first characterize it using the NMR setup at ÂÜŔňÉç-Dearborn. After that, they’ll send the new compounds to the Ames National Laboratory, where they will be mixed in solution with substances that have well-known NMR profiles. By seeing how much of a boost in the signal the nuclei give off, they’ll know which new polarizing agents have the most potential to enhance NMR techniques.
Constantinides says some of his preliminary published research on this topic has shown a lot of potential for Blatter-type radicals, which is why the DOE has funded further work in this area. He says if all goes well, he’s hoping for two big applications: One, it’ll give materials chemists like himself tools for providing detailed characterizations of molecules which have been hard to study using other techniques. The even bigger payoff would be if one of the new molecules they create is suitable for use in MRI, which would give doctors much higher-resolution images of tissues and tumors.
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Story by Lou Blouin
