C-13 MR tracers show potential for functional diagnostics

June 14, 2004

Successful molecular imaging rests largely on two key factors: high signal-to-noise ratio, which makes molecules detectable at extremely low concentrations, and good resolution. No single imaging modality can fulfill both criteria at present. PET may achieve high SNR, offering detection down to molar concentrations of 10-11, but its image resolution is poor. MR imaging provides superior resolution but struggles to detect its target at molar concentrations lower than 10-3.

A new MR technique under development promises to combine the best of both worlds, according to speakers at a New Horizons session at the European Congress of Radiology in March. Hyperpolarized carbon-13 nuclei can generate high-resolution images with the specificity commonly associated with PET. Promising experimental animal studies may eventually lead to MR-based tissue viability assessments and quantitative perfusion studies for routine clinical use.

C-13 imaging can be performed on a standard MR scanner, provided it is able to "listen in" to the lower radio-frequency resonance of C-13 molecules, said Dr. Klaes Golman, a professor of experimental radiology at Lund University in Sweden and general manager at Amersham Health R&D in Malmo. Golman advocates a technique known as dynamic nuclear polarization to create the tracers, which can be made from a wide range of biocompatible organic molecules. The chosen substance is mixed with salt, frozen to about 1 Kelvin, microwaved (to transfer polarization from electrons to the nuclei), and added to warm water ready for injection.

Suite of the Future

Golman envisions an MR suite of the future with a scanner placed adjacent to a ready-to-use C-13 drug delivery system. Radiologists would press a button to select an appropriate tracer, which would be polarized in situ and delivered directly to an injection syringe.

MR performed with a hyperpolarized C-13 tracer in a 1.5T unit produces 25,000 times as much signal as standard proton imaging, he said. But the benefits are not without a cost. C-13 tracers have short T1 relaxation times, due to rapid onset of depolarization.

"You cannot inject the C-13-containing substance into a human and have it stay polarized for a long time," Golman said. "You have to work very fast because signal will disappear within a minute or so. But this should be enough time to examine what you want, because you have so much signal to start with."

Applications for C-13 MR imaging are evolving through animal imaging. A rat study using hyperpolarized pyruvate has revealed a promising role for C-13 imaging in evaluating tissue viability. Pyruvate is metabolized to alanine and lactate in the body's muscles. The overall metabolic rate and the proportion of each metabolite produced can indicate whether tissue is healthy, diseased, or cancerous.

"The signal is so strong that it allows you to do this real metabolic imaging," Golman said.

Hyperpolarized C-13 showed promise in another rat study as a blood pool MR contrast medium. The vena cava, heart ventricle, and several hepatic veins were clearly visible on the 2.35T MR images after an intravenous injection of dynamically polarized C-13. Golman noted in the journal Academic Radiology (2002;9[suppl 2]:S507-S510) that the smallest vessel visible in the study was about 0.5 mm in diameter.

Perfusion offers another important application for C-13 MR. Gadolinium-enhanced MR is already used to provide information about blood flow, blood volume, and mean transit time through the capillary system. But conventional MR techniques cannot provide the accurate, quantitative measure of perfusion that is possible with C-13 imaging, according to Prof. Freddy Stahlberg, a professor of MR physics at Lund University.

Gd-enhanced perfusion studies rely on changing signal from protons affected by the contrast bolus, rather than signal measurements from the gadolinium itself. The relationship between signal and concentration varies according to vessel architecture and contrast dose, and absolute perfusion is generally overestimated.

"Gadolinium is an indirect signal source, and we have a very complex relationship between signal and concentration," Stahlberg said. "This is not the case with C-13. We have a direct signal source, we measure magnetization from the tracer itself, and we get a very simple, linear signal/concentration relationship."

Rapid T1 signal decay is a significant issue if C-13 is to be used in perfusion studies, although the problem can be dealt with relatively easily, he said. The drop-off is analogous to that seen in PET as tracers undergo radioactive decay. Radiologists should be able to calculate the C-13 signal decay and compensate for this in their measurements.

The resonant frequency of C-13 is lower than that of hydrogen, so radiologists will also have to increase acquisition times. Field-of-view can be reduced, however, because the exam is focused only on the C-13 molecule itself.

Perfusion Studies

Stahlberg showed images of experimental perfusion studies in a rat brain in which C-13 MR produced quantitative mean transit time, cerebral blood flow, and cerebral blood volume values. The technique may have more potential outside the brain, where many tracers are diffusible, he said (see figure).

For example, a novel method known as bolus differentiation, in which RF pulses repeatedly destroy hyperpolarized signal, could eliminate problems with tracer diffusion in organs such as the kidney.

"C-13 offers more possibilities than we expected when we started doing these experiments," Stahlberg said. "Initially, we used conventional tracer techniques like bolus tracking or inflow or outflow models. But the mere concept of having a hyperpolarized substance has allowed us to invent new tracer kinetic models."