Hyper-CEST MRI Technique Is Much Faster, More Selective

Conventional magnetic resonance imaging (MRI) is an outstanding diagnostic tool but one that suffers from low sensitivity, requiring patients to remain motionless for long periods inside noisy, claustrophobic machines. A promising new MRI method, much faster, more selective in that it is able to distinguish even among specific target molecules, and many thousands of times more sensitive, has now been developed.

The key to the new technique is called temperature-controlled molecular depolarization gates. It is based on a series of previous developments in MRI and the closely related field of nuclear magnetic resonance (NMR, which instead of an image yields a spectrum of molecular information) by members of the laboratories of Drs. Alexander Pines and David Wemmer at the U.S. Department of Energy's (DOE) Lawrence Berkeley National Laboratory (Berkeley, CA, USA) and the University of California at Berkeley (USA).

The technique was developed by a team of past and present Pines and Wemmer lab members headed by Dr. Leif Schröder of Berkeley Lab's Materials Sciences Division and including Drs. Lana Chavez, Tyler Meldrum, Monica Smith, and Thomas Lowery. The researchers outlined their results in May 2008 in the online international issue of the journal Angewandte Chemie.

"The new method holds the promise of combining a set of proven NMR tools for the first time into a practical, supersensitive diagnostic system for imaging the distribution of specific molecules on such targets as tumors in human subjects,” said lead author Dr. Schröder, "or even on individual cancer cells.”

Xenon is particularly useful in MRI and NMR because the spins of its nuclei are readily polarized, in a process involving contact with rubidium vapor irradiated with a laser beam. In such "hyperpolarized” xenon, the excess of spin-up nuclei can be as much as 20%, which gives a far stronger signal than hydrogen's 0.001% spin-up excess. Moreover, hyperpolarized xenon has a much longer relaxation time than hydrogen.

The final advance underlying the new technique is called Hyper-CEST: hyperpolarized xenon chemical-exchange saturation transfer. While biosensors can bring the xenon to specific molecular targets, in realistic applications relatively few of these are present, only about one percent compared to the total amount of free xenon injected near that target. The signal from the polarized xenon inside the biosensor cages is consequently much fainter than that from the uncaged polarized xenon nearby.

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.

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

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. Moreover, increasing temperature dramatically increases chemical exchange rates.


Related Links:
Lawrence Berkeley National Laboratory
University of California at Berkeley