Warming up for magnetic resonance imaging

The trick then is to depolarize the xenon nuclei in the immediate vicinity of the cages, which will serve to outline the target in high contrast against the surrounding hyperpolarized xenon pool. This is done through chemical exchange, as xenon atoms are constantly entering and leaving the biosensor cages.

A polarized xenon atom from the pool enters the cryptophane cage, which alters the xenon's resonance frequency, allowing it to be depolarized by rf radiation tuned to a specific frequency. The depolarized xenon atom is then exchanged for a new, incoming polarized atom and reenters the pool. In this way the buildup of nearby depolarized nuclei quickly outlines the target.

Because it produces a much stronger signal, Hyper-CEST acquires images thousands of times faster than would imaging the caged xenon directly. Yet it retains the great advantages of cryptophane biosensors, including their ability to "multiplex," or detect different targets at the same time.

"Slight differences in cage composition, involving only a carbon atom or two, affect the frequency of the signal from the xenon and produce distinct peaks in the NMR spectrum," says team member Tyler Meldrum, of the Materials Sciences Division. "If we design different cages for different xenon frequencies, we can put them all in at once and, by selectively tuning the rf pulses, see peaks at the frequencies corresponding to each kind of cage."

The final step

The processes described above -- hyperpolarizing the xenon, caging it in biosensors, and building up depolarized xenon in the immediate vicinity of the target through chemical exchange and selective bursts of rf radiation -- led to the development of Hyper-CEST MRI. But until now, Hyper-CEST MRI has only been tested at room temperature.

Using biosensor cages as temperature-controlled molecular depolarization gates makes Hyper-CEST MRI possible at a range of higher-than-room temperatures. Because the technique regulates the exchange rate of hyperpolarized-to-depolarized nuclei through the cages, biosensors regulated this way have been nicknamed "transpletors," by analogy to the transistors that act as gates for the flow of electrons from source to drain in electronic systems.

Hyper-CEST at a range of temperatures has many advantages. Most basic is that biomedical MRI must operate at body temperature. Aside from this practical consideration, temperature determines the rates at which different kinds of cryptophane-cage hosts react with their xenon-atom guests. And increasing temperature dramatically increases chemical exchange rates.

"At room temperature, a xenon atom will stay approximately 50 milliseconds inside the cage before it leaves again," says team member Monica Smith, of Berkeley Lab's Physical Biosciences Division. "Approaching body temperature, the time inside the cage decreases by at least factor of 10."

The ability to achieve high-contrast images, multiplexed to identify a range of molecular targets, and to do so in a short time, offers many benefits to patients and physicians.