Richard Carson, Ph.D., Director of the Yale PET Center
Since it opened in 2007, Yale’s state-of-the-art Positron Emission Tomography (PET) Research Center has been the site of many brain imaging studies to understand the mechanisms underlying neuropsychiatric illness. PET uses novel radioactive drugs (radiotracers) given in trace doses to measure quantitatively a wide range of physiological and pharmacological functions in human beings and research animals. Investigators are now making use of the center for studies in cancer and diabetes, illustrating the versatility of this resource as well as its faculty and staff.
The recent acquisition of two additional scanners, one for use in human subjects and another for small animals—bringing the total to five scanners—has been critical in allowing the center to expand into cancer research. PET is often used in clinical settings to detect and monitor cancer, but there has been a shortage of novel radiotracers used in cancer research. The center is working with investigators from therapeutic radiology to develop tracers that measure hypoxia in tumors in both humans and rodents. Fluoromisonidazole, a tracer that is sensitive to the oxygen content in tissue, will be used in multiple scans to determine the effect of radiation therapy on the hypoxic status of tumors. “We use quantitative imaging to tell us about the cellular and molecular physiology and how that changes with treatment or when comparing patient populations to controls. We do this very well in the brain, and our vision is to do this just as well in cancer,” said Richard Carson, Ph.D., director of the Yale PET Center.
Cancer presents different challenges than brain disorders because tumors occur all over the body. In the case of lung cancer, for example, breathing causes the tumor to move, blurring its image. The center’s approach to this problem involves adapting some of the technology used for brain imaging—such as tracking head motion—and applying it to the lungs. Chi Liu, Ph.D., 2011 YCCI Scholar, and assistant professor of diagnostic radiology and of biomedical engineering, recently joined the center to further these efforts, bringing expertise in correction and modeling for thoracic motion. “We view some of our imaging data as six-dimensional,” said Carson. “There are three spatial dimensions; the time dimension for the tracer kinetics; and respiratory and cardiac motion [which] each add a new dimension to the problem.”
Diabetes is another area in which PET imaging has been successfully applied. Insulin-producing beta cells are dispersed in islets throughout the pancreas, which makes quantifying them a challenge. Gary Cline, Ph.D., associate professor of medicine (endocrinology), Kitt Falk Petersen, M.D., associate professor of medicine (endocrinology), and their colleagues were recently able to measure the loss of pancreatic islet cells in diabetic patients, which may help in the development of drugs to stop or slow the death of these cells. The team studied healthy patients and those with type 1 diabetes using a radiotracer targeted for the vesicular monoamine transporter type 2 (VMAT2), which is co-expressed with insulin in beta cells. PET scans were used to measure the binding of VMAT2, showing that it was 40 percent lower in diabetic patients than in healthy controls. The study appeared in the June 2012 issue of the Journal of Nuclear Medicine. Cline is currently collaborating with Kevan Herold, M.D., professor of immunobiology and YCCI’s deputy director for translational science, in evaluating different immunotherapies to halt the loss of beta cells in early-onset diabetes. He is also extending his work to type 2 diabetes.
Before working with the PET Center, Cline had used NMR or MRI to conduct clinical research. “Working with the PET Center was kind of a shift in thinking in terms of radioactive isotopes, which for these purposes is much more sensitive for detecting receptor-targeted imaging approaches,” said Cline, adding that the center’s staff can help with all the steps along the way when conducting research at the facility. “The PET Center’s staff and infrastructure is remarkable,” he said. “For a person like me who was completely new to PET, the constant input from Rich Carson, the medical staff and the PET researchers really made this research possible.”
PET images from Cline and Petersen’s study showing (a) high uptake of a tracer targeting VMAT2 in the pancreas and (b) reduced uptake in a type 1 diabetes patient.
The PET Research Center conducts ongoing work to develop new tracers, which can be a time-consuming process that involves the interplay between chemistry, biology, pharmacology, and pharmacokinetics. Yiyun Henry Huang, Ph.D., associate professor of diagnostic radiology and director of chemistry for the PET Center, focuses on developing novel radiotracers for the center; he has developed two unique tracers for kappa-opiate receptors that are being used to study depression and other diseases. One tracer acts as an antagonist while the other acts as an agonist. Many receptor proteins can exist in two states: high affinity, the active state, in which an agonist will bind; or low affinity, in which it won’t bind. The new tracers allow researchers to measure the total number of receptors as well as the number in the active state. “We believe this could be a powerful tool, since some diseases are not just reflected in changes in the number of receptors, but also how many of them are in the active state and how that changes with time,” said Carson.
In addition to the two new scanners, the center has added four new hot cells, making it more efficient to develop and produce new radiotracers. It expects to add an additional PET CT scanner dedicated to rodents in the spring. For those who would like to learn more about the PET Research Center’s applications, the center sponsors a monthly series called PET Talks. Information is available at http://petcenter.yale.edu/research/pettalks.aspx. Investigators who would like to initiate a human PET research protocol should visit http://petcenter.yale.edu/InformationforInvestigators/index.aspx, which offers a guide and lists the main steps involved.