The Future of Molecular Imaging

Outside of a few words muttered in a cardiology catheterization lab, few patients may have heard of the technique known as “molecular imaging.” Yet the technique, which began in the context of nuclear medicine around the middle of the last century, may be so adaptable to modern advances in nanotechnology and gene therapy that it may be applicable to diseases as diverse as diabetes and Alzheimer’s.

Although there are now multiple organizations encouraging research into molecular imaging, such as the new World Molecular Imaging Society (WMIS), the Society of Nuclear Medicine remains a mainstay conference for researchers in the field, and oncology remains the main area of medicine affected by molecular imaging.

A Brief History

The science and practice of molecular imaging began with the beginnings of the nuclear age. “Molecular imaging began to be called that in the late 1990s, but the practice of looking at molecular functioning in the whole body, in vivo, noninvasively, had been going on longer,” says Dave Piwnica-Worms, MD, PhD, professor at Washington University School of Medicine in St. Louis, and director of the BRIGHT (Bridging Research with Imaging Genomics and High-Throughput) Institute at the university. “Right after World War II, the first form was the injection of I 131, a radioactive iodine, which was taken up by sodium iodide transporter in thyroid cancer patients.”

According to Piwnica-Worms, modern methods of using the technique include radioactive isotopes, positron-emitting isotopes (PET), single photon emission computed tomography (SPECT) and newer methods such as fluorofores (used for optical imaging) and even bioluminescent agents such as firefly luminescence.

Notwithstanding the hoopla, most of the groundbreaking work going on in the molecular imaging field is in the basic science area, and application to humans is sometimes years away. It’s still big news when an agent is approved by the U.S. Food and Drug Administration (FDA) or approved for reimbursement by government payers. For example, three years ago, a trade organization known as the Academy of Molecular Imaging was helpful in getting fluorodioxiglucose (FDG) scans, initially used in staging lung cancer, approved for reimbursement by Medicare — the first such approval ever, according to Robert Gillies, PhD, first president of the WMIS and vice chairman of radiation at the Moffitt Cancer Center in Tampa,Fla.

Perhaps counterintuitively, the biological nature and age of some of the first-generation agents currently approved for use and reimbursement in molecular imaging means that some of them are generic in nature. “There are in excess of two million U.S. studies per year done with FDG, which is a sugar where the radioisotope F18 is substituted,” says Thomas Tulip, PhD, a business manager with experience operating medical imaging companies from the early days. “This tracer helps identify metastatic distal lesions, because the tumor is growing rapidly and requires more energy, and the modified glucose serves as fuel for the energy-demanding cancer cells.”

Notwithstanding the widespread use of FDG, it is a generic tracer, says Tulip, who has been chief business officer for Dublin, Ohio-based Neoprobe for less than six months. “This material is an isotope that decays, with a 109-minute half-life, so it needs to be prepared relatively close to the location of ultimate patient use,” explains Tulip, who notes that FDG is prepared by about 10 companies, and manufactured in 100 commercial centers.

While no one company owns the right to FDG, which was developed in the academic setting and made its way through the FDA through a consensus process involving a review of the literature, a number of new proprietary agents are now in the stages of research or being submitted to the FDA, such as a small molecule designed for the detection of plaques related to Alzheimer’s disease, submitted to the FDA by Avid Pharmaceuticals, says Tulip.

“People are also developing tracers to look for active plaques in the heart system,” says Piwnica-Worms, of Washington’s BRIGHT Institute. “They are looking at receptors like myeloperoxidase in the blood vessels or on the heart cells to distinguish active plaques, which are more likely to burst, from stable plaques.”

Now, says Piwnica-Worms, people have begun to combine the tools of gene cloning with tracers, noting that the BRIGHT Institute itself has been involved in the discovery of luciferase, an experimental imaging agent related to fireflies.

Consolidation May Spur Research

The increase in molecular imaging research in recent years has led to a number of changes in scientific and medical organizations in the field, including the consolidation of many organizations into the WMIS, which met for the first time in September in San Diego. “As of [September], the Academy of Molecular Imaging [merged] with the Society for Molecular Imaging [SMI] to form the WMIS,” says Kim Pierce, executive director of the academy, which was formed in the 1980s as the Institute for Clinical PET. “The SMI was focused on basic science, while the academy focused on clinical applications,” says Gillies. “The society was also heavily invested in optical imaging.” Gillies notes that 40 percent of the society’s members are involved in optical imaging.

Eventually, scientists expect the consolidation to affect the WMIS conference attendance and program. “Attendance is about 1,000 now, and in one year, we’d like to see it increase by 20 percent, and in five years, by 50 percent,” says Dr. Paula Foster, PhD, a professor in the department of medical biophysics at the University of Western Ontario in London, who volunteers as chair of the program committee for SMI. This first year, the WMIS reflected many new areas of research, and it hosted a plenary session in conjunction with the Juvenile Diabetes Research Foundation. And, Dr. Foster says, in addition to areas of new research, she “could also see the program increase. Now, we have one day of education sessions and three days of scientific sessions, but I could see another day getting added on to the calendar. The new organization may also involve interest groups based around different modalities, or different disease categories. They may meet every evening during the meeting, and the WMIS may help them get set up organizationally and with fundraising, so eventually they may have their own meeting.”

Innovative Molecular Imaging Research

Today, medical researchers enjoy two experienced scientific organizations at which to present their molecular imaging research. In addition to the World Molecular Imaging Conference, WMIS’ annual meeting, the Society for Nuclear Medicine (SNM), which met this past June in San Antonio, hosted innovative presentations on the use of molecular imaging technology in disease states like Alzheimer’s, immunological disease and breast cancer.

Neurology. “The plaque which is important in Alzheimer’s disease is a little protein that clumps together and forms tiny lumps outside the neurons, called amyloid beta,” says Christopher Rowe, MD, PhD, professor and director of nuclear medicine at the Center for PET at the University of Melbourne,Australia, who presented his research in the area at SNM and at the International Conference on Alzheimer’s Disease in Paris this past summer.¹ “We can use PET studies to look at amyloid beta, a technique which was first developed at the University of Pittsburgh and in Sweden in 2002. If we’re looking at the metabolism in the brain, we can use a radioactive form of glucose. The damaged areas of the brain have much less metabolism, so you will see a defect in those areas in a picture of the brain.”

Although the presence of amyloid beta plaques correlates strongly with the risk of future Alzheimer’s development, the course of the disease may be slow, suggesting the importance of early therapy should one of the experimental therapeutic agents for Alzheimer’s disease ultimately be approved for general use, according to Rowe. For now, however, the use of molecular imaging in identifying amyloid beta plaques will be most useful as a diagnostic tool, he explains, adding that new techniques may be available clinically in the U.S. in the next year.

Data from clinical trials of an experimental agent known as Florbetapir were submitted to the FDA by Avid Radiopharmaceuticals and published in the Journal of the American Medical Association. Other agents also are being developed, such as florbetaben by Bayer and Flutemetamol by GE Healthcare, Rowe says.

Immunology. Other research, presented at SNM by Piwnica-Worms of the BRIGHT Institute, may lead to advances in stem cell transplants, a new frontline therapy for some immunological conditions.² Piwnica-Worms and colleagues have published some research into molecular imaging in bone marrow transplant recipients. The technique has both diagnostic and therapeutic applications, and is beginning human trials, he explains.

“This research will look at bone marrow transplant patients who have leukemia or lymphoma,” says Piwnica-Worms. “They get the transplant to kill off all the native bone marrow, then you give them the graft, in this case, an allogenic transplant from another donor. Now, we can use PET imaging to track where the cells go in the body,” he says, adding that the trial was just approved to open up in humans. The technique has been tried in two human patients, and the researchers hope to get 10 enrolled in the Phase 1 observational trial.

“We hope we’ll be able to follow whether the stem cells go to the spleen, liver or lung before going to the bone marrow,” Piwnica-Worms explains, noting that one of the main risks of a bone marrow transplant is the danger of graft-versus-host disease (GVHD). “There’s a danger that if the graft is a nongenetically matched donor cell, it can turn on the recipient. But the way this experimental retroviral construct is formed, it has a herpes simplex virus and kinase incorporated into it. If a patient got graft-versus-host disease, these donor lymphocytes have been engineered with a suicide gene delivered by the retrovirus, which when combined with a drug like gancyclovir would wipe out the donor lymphocytes that are producing the GVHD. Now, we’ve wiped out the bone marrow transplant, so they’re back to the ICU, but at least they’re still alive.”

Oncology. Molecular imaging continues to spur new research in the oncology field. According to Tulip of Neoprobe, research in the field may result in not one, but two new agents for sentinel lymph node mapping coming onto the market in the next year. “Traditionally, in breast and lung cancers, one has surgery to excise some of the cancerous tissue, and one needs to understand how far the cancer has spread,” says Tulip. Previously, surgeons have used only an agent called blue dye in such procedures, because it was the only agent approved by the FDA for lymphatic mapping — until August, when the FDA approved another agent called sulphur colloid. But, both blue dye and sulphur colloid possess limitations, Tulip explains. “The [blue dye] injection frequently is painful, and there are some allergic reactions,” he says. And, “some percentage of women actually get tattooed in the nodes with the blue dye. But the most important element with blue dye is the 10 percent to 20 percent false negative rate. Sulphur colloid also has a non-negligible false negative rate, and it has some issues as to how long it takes until it clears the injection site.” But, with Neoprobe’s experimental product, Lymphoseek, the sulphur colloid cleared the injection site within a matter of minutes, even though it was in the lymph nodes, whereas the process can easily take hours.

Neoprobe submitted a new drug application to the FDA last week for Lymphoseek, based on results from clinical trials presented at this year’s meetings of the American Society of Clinical Oncology and SNM.^3,4

High Expectations for the Future

With researchers now combining molecular imaging with the latest advances in gene therapy and personalized medicine, what was once an enigmatic outpost of the nuclear age, generating diagnostic agents that were generic almost by nature, may have finally hit its stride.

With researchers now combining molecular imaging with the latest advances in gene therapy and personalized medicine, what was once an enigmatic outpost of the nuclear age, generating diagnostic agents that were generic almost by nature, may have finally hit its stride.

Whether the experimental uses of the techniques discussed above will ever make it into clinical use in humans is unknown for now, but with new mergers and associations coming to the field, it is clear that expectations are high.