Mapmakers of the living human body

Imagine trying to develop a drug and being able to see how and where that drug acts inside the body of a living person. Just such a tool is provided by positron emission tomography (PET), an imaging technology that is aiding drug development and research on the mechanisms of disease at the School of Medicine’s state-of-the-art PET Center.

Animal models are useful for many aspects of biological research, but when the aim is translating research discoveries into applicable treatments for humans, particularly for brain disorders, research in living humans is critical. “It’s only through imaging that you can begin to understand the complexity of the human brain,” says Robert S. Sherwin, M.D., the C.N.H. Long Professor of Medicine and director of the Yale Center for Clinical Investigation (YCCI).

It is precisely the inaccessibility of the human brain that makes in vivo imaging technologies like PET so valuable. “If you suffer from an illness of nearly any organ of your body, it’s perfectly acceptable to donate a piece of that organ for analysis” via biopsy, says John H. Krystal, M.D., Robert L. McNeil Jr. Professor of Translational Research and chair of the Department of Psychiatry. “But the preciousness of brain tissue has prohibited psychiatry from developing the kind of understanding of the organ that it studies relative to what is possible in other areas of medicine.”

In addition to the critical role it has played in neuroscience research at Yale, PET is now beginning to see wide use in research on diseases such as cancer and diabetes.

Led by Richard E. Carson, Ph.D., professor of diagnostic radiology and biomedical engineering, the PET Center’s mission—to provide the highest quality of nuclear imaging to the medical school’s researchers—is embodied in numerous collaborations both on campus and off, all relying on an intricate and well-choreographed network of technology and personnel.

At the heart of the 22,000-square-foot facility is a cyclotron, which accelerates atomic particles to produce short-lived radioactive isotopes. A team of radiochemists led by Yiyun Henry Huang, Ph.D., director of chemistry at the Center and associate professor of diagnostic radiology, uses these isotopes to synthesize radioactive versions of drug molecules or other biologically active substances. These radioactive molecules are called tracers: they trace the paths of molecules that are important in human physiology, such as glucose, and they’re administered to research subjects in extremely small, trace amounts.

A subject lies within a PET scanner (similar in appearance to a CT scanner) while radiochemists, working under great time constraints due to the short half-life of PET isotopes, create the labeled compounds. When these compounds are injected into the subject’s body they navigate and bind to specific organ sites. The PET scanner is able to detect the accumulation of radioactivity at these various sites and convert this data into color-coded maps. But PET provides more than pretty pictures: the images are based on precise quantitative physiological and pharmacological information that can be useful in its own right.

In psychiatry, imaging technologies like PET have enabled some of the most critical discoveries in recent decades. Since the early 1960s, psychiatrists had hypothesized, for instance, that psychosis—a set of symptoms seen in schizophrenia that includes hallucinations and delusions—was a consequence of hyperactivity of the brain’s dopamine signaling system. “But until recently, we had no way to test that hypothesis,” Krystal says. This changed in the 1990s, when new research approaches in imaging made it possible to measure dopamine release noninvasively in a living person. “Now that we have PET,” Krystal says, “we’ve identified a number of pathological mechanisms that might be targeted with treatments for psychiatric disorders.”

In the quest to find such treatments, brain imaging has become essential. Single-photon emission computed tomography, or SPECT, is a complementary imaging tool (often used during cardiac stress tests) that is more widely available than PET and does not require a cyclotron, because SPECT tracers, often based on iodine or technetium, are longer-lived and can be ordered from suppliers. But PET has become more popular thanks to the development of the PET isotope Fluorine-18, which has a longer half-life than most PET tracers and is widely used in clinical cancer settings. PET instrumentation is expensive, but it offers a number of advantages over SPECT: the cost per study is lower; spatial and temporal resolutions are higher; imaging is more sensitive and contains less “noise”; and a greater variety of tracers can be used.

Kelly P. Cosgrove, Ph.D., assistant professor of psychiatry, uses PET to study the effects of nicotine-induced dopamine release in the brain. In 2009, a team including Cosgrove, Irina Esterlis, Ph.D., assistant professor of psychiatry and diagnostic radiology, and the late Julie Staley-Gottschalk, Ph.D., published a study in Archives of General Psychiatry in which they used SPECT imaging to demonstrate that, after quitting, smokers have an increase in nicotine receptors that lasts up to a month, and that this increase in receptor availability is correlated with craving for cigarettes.

Cosgrove, also assistant professor of diagnostic radiology and neurobiology, is building on that work, using PET to study effects of variables like sex, psychiatric status, and genetic makeup on nicotine-induced dopamine release, as well as cognitive changes that occur when a person stops smoking.

Krystal has used PET to examine the effects of post-traumatic stress disorder and early emotional trauma on the brain. Others in the Department of Psychiatry are using PET to study depression, schizophrenia, Tourette’s syndrome, and various addictions.

Marc N. Potenza, M.D., Ph.D., uses PET to analyze brain reward circuits in cocaine, alcohol, and gambling addictions. “PET offers distinct advantages over other widely used imaging measures in that it allows for investigation of specific receptors,” which is “critical to understanding pathophysiology, particularly with respect to developing new pharmacotherapies,” says Potenza, professor of psychiatry, neurobiology, and in the Child Study Center.

Yale Cancer Center (YCC) is one of the PET Center’s newest partners in research applications outside psychiatry. Like YCCI, which has provided significant funding and other resources to help initiate collaborative work, YCC has contributed pilot funding to facilitate collaborations using PET.

One such project involves work by Joseph N. Contessa, M.D., Ph.D., assistant professor of therapeutic radiology, who is using PET to analyze the actions of the anti-cancer drug erlotinib (Tarceva) in non-small cell lung cancer by labeling erlotinib and using it as the PET scan tracer.

Others at YCC—including David J. Carlson, Ph.D., assistant professor of therapeutic radiology, and Sara Rockwell, Ph.D., professor of therapeutic radiology and pharmacology, and associate dean for scientific affairs—are using newly designed PET tracers to study hypoxia (low levels of oxygen) in the tumors of both humans and mice.

PET has also proven valuable in assessing recovery from spinal cord injury. In 2011, Stephen M. Strittmatter, M.D., Ph.D., the Vincent Coates Professor of Neurology and professor of neurobiology, published a paper in Annals of Neurology showing that after treatment with an agent that unlocks regeneration mechanisms in the nervous system, mice with spinal cord injury showed marked recovery, which Strittmatter’s team observed by using PET to measure the density of nerve fibers, using a tracer originally developed to study depression. His work may lead to new treatments for spinal cord injury in humans.

One of PET’s benefits is the unlimited potential of radiochemistry to create and test new labeled compounds. As in Strittmatter’s research, often a compound will turn out to have important unexpected uses. In recent studies led by Gary W. Cline, Ph.D., associate professor of medicine, Kitt Falk Petersen, M.D., professor of medicine, and Kevan Herold, M.D., professor of immunobiology and medicine, researchers found that a tracer originally designed to measure neural activity in Parkinson’s Disease could be used to measure the mass of insulin-producing ß-cells in the pancreas. “The ability to look at and measure them in vivo in human beings over time is a hugely valuable tool” for diabetes research, Carson says (see figure).

As noted, PET is extremely valuable in drug design, and the ability of the PET Center’s radiochemistry team to create a wide range of tracers underlies a mutually beneficial relationship the Center enjoys with the pharmaceutical industry. Pfizer contributed $5 million in 2007 to help establish the Center and the company provides ongoing support for PET studies of its large library of compounds. The expertise of PET Center scientists has now spurred collaborations with more than 10 pharmaceutical companies.

But the Center’s relationship with industry is equally beneficial for Yale scientists. Having been designed to accommodate industry studies—which typically occur at a faster pace and larger scale than federally funded academic studies—the Center has the advantage of high-quality instrumentation.

The Center has a scanner able to image the human brain at a resolution of 2.5 millimeters, for instance, one of only 17 such scanners in the world. The scanner can also track and compensate for patients’ head movements 20 times per second to eliminate blurring.

And the Center’s advanced chemistry facilities mean that scans can often be scheduled so closely that a tracer can be produced and then quickly used in two or more scans. For that to happen, “there are a lot of different parts working together,” says Evan D. Morris, Ph.D., co-director for imaging and associate professor of diagnostic radiology, biomedical engineering, and psychiatry.

Since its 2007 opening, the Center has increased its capacity by acquiring new PET scanners and growing its staff to more than 50, placing it among the largest, most active centers in the U.S.

The Center’s abundance of resources are not only of immediate benefit for Yale research, but also enables School of Medicine scientists to make stronger cases when requesting grant funding. Says Carson, “When you’re competing for grants in an always-difficult grant environment, it’s helpful to be able to say, for instance, that we have the highest-resolution PET scanners available in the world.”