Medicine in Motion
A Spin Through UAB’s New Cyclotron
By Matt Windsor
Imagine you want to find tiny outposts of cancer, track the growth of Alzheimer’s plaques, or detect early signs of heart disease—things that you just can’t do with a traditional MRI or CT scan. One way would be to attach a homing device to a normal body compound, like glucose, insert it into a patient, and see where it goes. That’s positron emission tomography (PET) imaging in a nutshell.
The first step is making the homing devices. In the PET world, they’re known as tracers, and to produce them you’ll need a cyclotron. Cyclotrons make tiny particles go very fast. Using paired magnets, they accelerate protons and other particles to more than a million miles per hour, then shoot them in a beam at a target just outside the machine.
The goal is to convert a stable element into another, unstable element—that is, to make a radioisotope. The more power you have, the more isotopes you can make, and the more body processes you can image. UAB’s 24-million electron-volt cyclotron, which was installed in April 2013 as the centerpiece of the new Advanced Imaging Facility in the Wallace Tumor Institute, is the most powerful cyclotron at any U.S. academic medical center.
Just across the hall from the cyclotron are two state-of-the-art PET/CT scanners, the only ones of their kind in Alabama, which can image patients much more quickly than UAB’s previous machines, at half the radiation dose. Next to them is a bay being prepared for a cutting-edge PET/MRI machine, a research tool that offers revolutionary neural imaging capabilities.
“What makes this facility transformative is the proximity of the cyclotron to the PET/CT units and eventually to the PET/MRI,” says Cheri Canon, M.D., chair of the UAB Department of Radiology.
That’s because distance matters in PET imaging; radioactive tracers don’t last long. The most commonly used PET compound, F18 FDG, is a glucose molecule labeled with Fluorine 18. It is widely used in cancer staging and diagnosis, and it has a half-life of 110 minutes. “In other words, after 110 minutes, half of it is gone,” says Kurt Zinn, Ph.D., director of the UAB Division of Advanced Medical Imaging Research. Before the cyclotron went active in October 2013, UAB received daily shipments of F18 in order to keep its PET scanners in operation.
The size and power of the cyclotron mean it can produce large amounts of F18 FDG. “But it also allows us to make more exotic tracers,” Zinn explains. And the close proximity of the scanning suites to the cyclotron makes it feasible to use these extremely short-lived agents for both patient care and research.
How short-lived? Carbon 11, which can detect damaged neurotransmitters in patients with Parkinson’s disease before symptoms appear, has a half-life of 20 minutes. Oxygen 15 tracks blood flow in incredible detail; its half-life is two minutes. “They’re gone so fast you barely have time to take the picture,” says Janis O’Malley, M.D., director of UAB’s Division of Molecular Imaging and Therapeutics. Special tubes take Oxygen 15 gas directly from the cyclotron to a patient waiting in the PET/CT scanner.
PET is “incredibly useful for looking at cancer,” O’Malley says. “It lets you more precisely monitor the effects of therapy,” for instance, she explains. “It will tell you if a chemotherapy drug is working, so you can change to something else quickly if it isn’t.” In several cases, an initial (non-PET) CT scan showed that a patient’s tumor hadn’t changed in size, “but we knew from the PET/CT that the cancer therapy was working because it had killed the activity in the tumor,” O’Malley says. “We’ve also seen the opposite: The mass was getting smaller, but we could tell that new lesions were popping up."
“New tracers are being developed all the time, further expanding the clinical applications for advanced imaging,” O’Malley says. One cardiac agent now in phase 3 clinical trials, florpiradaz, offers a “much more precise look at what’s going on” in the heart compared to standard cardiac stress tests. That allows doctors to better identify patients at risk for an impending heart attack, O’Malley says. Other agents could improve “viability studies,” which examine heart tissue after an attack in order to determine if there is enough healthy tissue to warrant a bypass. “If we can determine that an area we thought was all scar tissue in fact has healthy tissue, we could save it with surgery,” says O’Malley. “We can get the blood flowing back to that area and allow it to recover.”
The cyclotron produces compounds for patient imaging in the morning; the rest of the day it is set aside for researchers, who are working on newer and more long-lasting tracers. “The neuroscience area in particular has tremendous potential, because you can detect signs of malfunctions in the brain long before there’s ever a clinical symptom,” Zinn adds. “Then you have the opportunity to intervene, and use PET to follow that intervention to see how it is working.” UAB researchers are particularly interested in finding ways to combine the precision of tracers such as Carbon 11 with the longer half-lives of agents such as Zirconium 89, which can be imaged more than a week after administration.
The Advanced Imaging Facility is already serving as a premier recruitment tool for the brightest clinical and research minds, adds Canon. “This facility gives our physicians and researchers opportunities in clinical care and research that they could not get anywhere else,” she says. “It’s really unmatched.”
Now You See ItA few of the powerful—but short-lived—tracers produced by UAB's cyclotron:
Zirconium 89 • Use: Detecting cancer metastases • Half-life: 3.2 days
Fluorine 18 • Use: Cancer staging, detecting metastases, evaluating tumor treatment response • Half-life: 110 minutes
Carbon 11 • Use: Early detection of plaques in Alzheimer's disease and neurotransmitter changes in Parkinson's disease • Half-life: 20 minutes
Ammonia 13 • Use: Cardiac perfusion (blood flow) studies • Half-life: 10 minutes
Oxygen 15 • Use: Cardiac perfusion • Half-life: 2 minutes
A Day in the Life of the Cyclotron Team
Long before daybreak, Harvey Doane is hard at work in the UAB Advanced Imaging Facility (AIF), preparing UAB’s cyclotron for another day of service. The massive blue device, which weighs more than 61,000 pounds, produces the radioactive particles needed for positron emission technology (PET) imaging. These particles, known as tracers, decay rapidly; within a few hours, they are gone.
That’s why Doane arrives around 3 a.m. to prepare the cyclotron for action, adjusting his target material and settings based on the number of patients being scanned that day and the types of scans required. As the cyclotron begins bombarding the target material with a beam of protons, the facility’s radiopharmacist and radiochemist meticulously clean the adjoining “hot cells” in which they will finish transforming a stream of tracer product into a patient-ready pharmaceutical.
The most common radiopharmaceutical is F18 FDG—a combination of the tracer Fluorine 18 and glucose—which is used in cancer diagnosis and staging. Producing F18 FDG takes about two hours of cyclotron time and another two to three hours of preparation time before it reaches the patient, says Denise Jeffers, the AIF’s radiopharmacist.
An inert gas pushes the F18 from the cyclotron through tubes in the floor into chemistry synthesizers, where it is bound to glucose molecules by an automated process under the watchful eye of radiochemist Jinda Fan, Ph.D. The resulting F18 FDG is then transferred to Jeffers’s hot cell, where she uses robotic manipulator arms to prepare the appropriate dose for each patient who will be scanned that morning.
By the time patients arrive at 7 a.m., their radiopharmaceutical doses are ready. For F18 FDG, it takes an hour or more after injection for the dose to spread throughout the body. Patients wait in private, TV-equipped rooms until the dose has reached the appropriate areas; then they are scanned in the facility’s “time-of-flight” PET/CT scanners, the most advanced PET cameras in Alabama.
Meanwhile, the cyclotron, hot cells, and other machinery is thoroughly scrubbed and sterilized—“you’d better like cleaning if you want to do this job,” Jeffers says—to get set for their next jobs: producing experimental tracers for UAB researchers.
“The most interesting things we can do aren’t with F18, but with what are called ‘intrinsic labels’”—small molecules that behave identically to their non-radioactive counterparts, says Kurt Zinn, Ph.D., director of the UAB Division of Advanced Medical Imaging Research. “For imaging receptors in the brain, for example, the neurotransmitters are so small that only an intrinsic label such as Carbon 11 will reach them. We can produce Carbon 11 and other exotic labels with our cyclotron, unlike any other facility in Alabama.”
“The most important aspect of this cyclotron is what it means to our patients now and in the future,” says Cheri Canon, M.D., chair of the UAB Department of Radiology. “Because of the different types of radioisotopes that can be produced in our cyclotron, we can cover the whole gamut of disease, from diagnosis to assessing response to treatment.”