A patient lies on a table that slides slowly through a PET scanner. Radioactive signals are recorded by detectors in the scanner and are later converted into three-dimensional computer images of tissue concentrations and organ function.

PET Center Exemplifies Cutting-Edge Technology, Strong Partnership with Industry

With the opening of the Yale PET Center, doctors, scientists, and students now have a fast, and accurate way to take three-dimensional pictures of the living brain and other parts of the body.

PET, or Positron Emission Tomography, is a scanning technique that provides images of organs as they function. PET scans are obtained with the help of radiotracers, readily detected chemicals that bind to target sites in the brain and body so that they can be viewed. These highly sensitive scans help doctors identify and treat disease, and they allow researchers to determine whether drugs under development are reaching their intended targets.

Pfizer, Inc., a partner with Yale in the Yale-Pfizer Bioimaging Alliance, contributed to the establishment of the Yale PET Center. Located at 801 Howard Avenue, the Center is in close proximity to other Yale School of Medicine departments and the Pfizer Clinical Research Unit in New Haven. “The PET Center exemplifies Yale’s commitment to cutting-edge research and strong partnership with industry,” said Yale President Richard C. Levin.

PET Center Director J. James Frost talks about the history of PET, why its important to the Food and Drug Administration, and how work being done at the Yale center could lead to what he sees as the holy grail of PET research: personalized medicine.

PET Center Director J. James Frost, M.D., Ph.D., MBA, professor of diagnostic radiology and psychiatry and chief of nuclear medicine at Yale-New Haven Hospital.

Q: How do imaging techniques like PET open doors to new treatments and medications?

A: The development of new medications is an arduous, expensive process. Based on the experience of the pharmaceutical industry, we know that only a small percentage of drugs taken out of discovery to clinical trial make it as approved drugs. We’d like to increase the number of drugs that make it. It’s very expensive to take a drug to a clinical trial and have it fail.

Q: So, how do we better predict which drugs will be successful?

A: With PET we can see whether the drug molecules get into the organ of interest, for example, into the brain. If it doesn’t get into the target organ, it won’t be successful. After that, once it is in the brain, does it bind to the correct site? With PET, we can actually see where the drugs are binding to different molecular targets in different parts of the brain. After that, the question becomes, is the drug targeting the receptor in sufficient quantities? Too little would make it less effective. Too much might cause side effects. PET can tell us that. We can tell exactly what percent of the receptors are being occupied at each dose.  We can then take the information we get from PET scanning and design a big clinical trial with hundreds or thousands of patients, knowing we are in the sweet spot for the dose.

Q: At your recent opening, George Mills, the director of the Division of Medical Imaging and Radiopharmaceutical Drug Products of the U.S. Food and Drug Administration, talked about the importance of PET imaging. Why does the FDA consider PET important?

A: After we work with drug companies to help them design clinical trials, we can take that same information and use it to get the drug approved at the FDA level. When you do a big expensive clinical trial, you are looking at symptoms as reported by the people being studied; you have to take the placebo effect and the vagaries of subject reporting into consideration. Is the effect a true effect, or is there an effect because the subject thinks there will be one? If you have a PET scanning agent, you can biochemically demonstrate the effect of the drug. You can advance knowledge around the efficacy of the drug and speed up its approval. The FDA sees an acute need for this. 

Q: Can PET scanning also be used for disease diagnosis and monitoring treatment?

A: We do use PET scanning in disease diagnosis and treatment monitoring. One of the most commonly used PET scanning agents is 18F-FDG (fluorodeoxyglucose). It is used day-in and day-out with the PET scanner located in the clinical nuclear medicine section at Yale-New Haven Hospital. It can be used to detect some kinds of heart disease and many kinds of malignant tumors, including those of the brain, lung, breast, and colon. After diagnosis, PET can be used to monitor the response to treatment, often demonstrating biochemical changes that precede changes in the size of the tumor or metastases.

In addition to medication development, the PET research center is really focused on understanding the molecular basis of disease. What receptors are up and what receptors are down? What is the molecular basis of schizophrenia, of substance abuse, of depression? What systems are altered? We look at traits, such as genetics, or states, such as being depressed or taking cocaine. That’s where this field really started, trying to understand the mechanism of disease. It was only later that the drug companies realized it could be useful for their purposes, and that the FDA realized it could be useful for theirs.

In addition to working with drug companies and the FDA, we plan to develop new PET agents to be used as diagnostic imaging agents, to identify tumors, to monitor treatment response and to search for recurrent problems related to disease. Another question is which PET tracers will allow us to learn more about mental disorders. There might be different subtypes of mental disorders. That might be true of schizophrenia or depression. And then you finally get to the holy grail of all this, personalized medicine.

Radioactive atoms, which are attached to molecules and then used in the scanning process, are produced in a cyclotron machine, shown here.

Q: Tell us more about personalized medicine and how PET research will contribute to its development.

A: Personalized medicine uses information about a person’s genetic and biochemical profile to detect, treat, and prevent disease. Instead of taking a one-size-fits-all approach, personalized medicine would allow us to understand the specific subtype of disease a person is suffering from, what kind of drug will target that subtype of disease and what the optimal dose is.

Ideally, it will allow us to make the correct diagnosis, provide the right kind of therapy, and then monitor the response, adjusting the treatment as necessary. Instead of doing this with a hit-or-miss approach, as is sometimes necessary now, PET tracers might allow us to understand a patient’s condition at a molecular level, and tailor the treatment and medication dose to treat them effectively.

These tracers that we develop to understand disease—the same tracers that we use to help Pfizer and other industry partners, the same tracers we use to deal with the FDA—these become tracers to diagnose disease and direct treatment.

These tracers can not only be used to diagnose, but to differentiate between different subtypes of disease. For example, if a patient presents with hallucinations, we might be able to see that this is a change in the receptor known to be associated with schizophrenia, the dopamine D2 receptor. We’ll knowit is the D2 and not the D3, for example. So we can target the treatment to that specific molecular subtype of schizophrenia.

Q: The Yale PET Center is one of the few in the world that has a scanner with a resolution of 2.5 millimeters. Why is this equipment so rare at this point and what will this equipment allow the center to accomplish?

A: This is a scanner designed specifically for the human brain. The technology in this scanner is so complex that it would be prohibitively expensive to implement in a whole body scanner. It was built as a prototype and is one of only about eighteen in the world. It has very small detectors; everything is miniaturized.

In the human brain, high resolution is key. A lot of brain disorders start in small areas of the brain, in small clusters that then fan out into large areas. Alzheimers, Parkinson’s Disease, substance abuse. These all start in small areas of the brain.

With existing scanners with lower resolution images, we can see the larger areas where these diseases have fanned out. But we really want to see where they start. That is where higher resolution imaging comes into play. With this scanner, from about 6 or 7 millimeters, we can go down to 2.5 millimeters. This way we can see those little areas of the brain that cause a lot of trouble when they start to degenerate or undergo other changes.

Then, after we gather the data from this scanner, we have to reconstruct the data into an image. We have to acquire a lot of data to get that high resolution image. That is a process that is exceedingly computer intensive. So Rich Carson, our lead physicist, put a 46-node computer cluster together. With this cluster, we can reconstruct an image overnight. Otherwise, it could take a day or longer to do the same thing.

A vial of the labeled PET tracer undergoes final quality control, which includes calibrating the dose and ensuring purity. The Yale PET Center uses the high quality control standards used by the pharmeceutical industry in the preparation of medications. (Photos: Henry Douglas, Department of Diagnostic Radiology)

Q: The Yale PET Center is one of the few PET laboratories in the United States that is cGMP (current good manufacturing practice) compliant. What does this mean and why is it important?

A: This ensures the highest quality control standards for the radio label drugs that we make. Previously, all PET centers operated under pretty good standards to make sure the radio chemically tagged compound was pure and sterile, and that there were no bacterial fragments that could cause fever. While those standards were high, they were not as high at the standards that companies like Pfizer have to adhere to. So, while this is way beyond what a typical PET lab has to abide by for research, we were asked to do this by Pfizer. To work with them, they really require that. Eventually all PET centers will have to abide by these standards. But, with the help of Pfizer and our radiochemists, Dr. Yu-Shin Ding, the PET Center’s lead chemist, and Dr. Henry Huang, we already are up to the highest standards for a PET labaratory. This helps maintain a good relationship with Pfizer and allows us to work with other companies as well.