Diagnostic Imaging
November 2003

COMMUNITY PET

Niche agents fill in the gaps surrounding FDG

Nothing beats F-18 for versatility and convenience, but new tracers are in the works

As PET gains prominence, the search for new tracers is intensifying. But the greatest obstacles the next generation of tracers will face may have less to do with science and more with economic factors and a harsh-some say misguided-regulatory environment.

FDG is still the reigning champion among PET agents. This all-purpose tracer measures consumption of glucose and is therefore useful in determining the health of cells throughout the body. Cancerous cells, for example, consume more glucose as they proliferate, while the brain cells of patients with various neurodegenerative diseases show markedly different patterns of glucose consumption from those of healthy patients.

FDG is widely available at radiopharmacies throughout the country, and with a relatively long half-life of about 110 minutes, it is stable enough to use in almost any situation. What, then, will take its place? Nothing, according to Eric Roman, general manager of global radiopharmacy at GE Medical Systems.

"There is no such thing as the next FDG," Roman said. "The world will be filled with many tracers for very specific applications."

Two other radiotracers have passed regulatory muster at the FDA: sodium fluoride and nitrogen-13 ammonia. Both are available but are not widely used, said Carlos Gonzalez, Ph.D., vice president of Cyclotope, which produces tracers. Sodium fluoride is used for bone scans, while N-13 ammonia is useful as a perfusion agent for the myocardium.

N-13 ammonia has been approved for reimbursement, but Gonzalez does not expect it to gain widespread use because of its short half-life of only 10 minutes. For the tracer to be used effectively, the production facility and the medical facility must be in extremely close proximity.

"I do believe in the technique, but I think making N-13 ammonia commercially available in a wider area will be difficult," he said. "We know from experience that the technique is highly demanding, but I believe that given the right set of circumstances, it is a modality that can be implemented."

The next generation of PET tracers will face higher hurdles than FDG or N-13 ammonia did. Those two agents were among a group of five radiopharmaceuticals that gained approval from the FDA under unique circumstances just as the industry was developing, said Dr. Jorge Barrio, a professor of molecular and medical pharmacology at the University of California, Los Angeles. Instead of undergoing clinical trials, FDG, N-13 ammonia, fluorodopa, sodium fluoride, and oxygen-15 water were granted approval after an extensive literature review.

"All of them had been well studied and were very much in human use and had the potential to be used clinically," Barrio said.

New agents, however, will most likely have to undergo the same long, costly clinical trials that new therapeutic drugs face before they can gain approval. Barrio and others in the nuclear medicine community claim that the requirement is excessive and will inhibit development of new tracers.

"We need to convince the FDA that a diagnostic agent that's administered in nanomal quantities, and at the most several times in a patient's lifetime, shouldn't require the same toxicology as a drug that's administered in gram quantities every day of a patient's life," said Dr. Michael Welch, a professor of radiology at Washington University in St. Louis.

Regulatory requirements have not totally dampened researchers' interest in new PET agents, however. More than 400 abstracts, most concerning new radiopharmaceutical agents, were submitted to the 15th Symposium on Radiopharmaceutical Chemistry in August, Welch said. But he is not confident about their prospects in the near future.

"FDG was approved through a unique mechanism that, in my opinion, will never occur again," he said. "There are lots of tracers out there that are of great potential interest, but how you get them from the research stage to the clinical use stage is a big question."

INDUSTRY INVOLVEMENT

While academic researchers investigate and create new probes, the industry must take on the real task of introducing new radiopharmaceuticals for clinical use, Barrio said. And industry is starting to take notice. Cyclotope was founded in 2002 to take advantage of the new market for PET radioelements beyond FDG.

More established players are moving toward development as well. PETNET established the LA Tech Center, an alliance with UCLA, as a part of the company's move toward a more "pro-discovery" direction, said Charles Gluchowski, managing director of the Tech Center. The company plans to seek out or develop molecules that it can develop proprietary syntheses for and then distribute effectively. In particular, it is eyeing a few that appear to have a strong track record, which might speed regulatory approval.

Industry faces another hurdle before it gets involved in creating and marketing new tracers: Too many compounds don't have patent protection.

"I have a very large group developing PET agents, but up to five years ago, we never really bothered with patenting our compounds because PET was a sort of research cottage industry," Welch said.

The growing interest in PET means that research groups must become more protective of their intellectual property, he said. Otherwise, they face diminishing odds that their agents will ever be commercialized.

PROMISING NEW AGENTS

Fluorothymidine (FLT) is one of the most promising tracers. It ability to track tumor growth has generated a great deal of interest, said Dr. Hubert Vesselle, an assistant professor of radiology and nuclear medicine at the University of Washington. The excellent correlation between the level of FLT uptake and the proliferation rate of lesions in the lung implies that the agent may be particularly useful in monitoring the effectiveness of cancer treatments.

"FLT specifically focuses on the very nature of tumor growth," said John Grierson, a research scientist at the University of Washington, who helped synthesize the agent. "If the tumor is growing and cells are proliferating, this agent is specifically targeting the pathway involved with DNA synthesis."

Because it focuses on DNA replication instead of energy consumption, FLT may be more adept at tracing tumor growth than FDG in some cases, Grierson said.

To find the next PET agents, scientists at UCLA and the LA Tech Center are focusing on therapeutic drugs, said Dr. Michael Phelps, chair of molecular and medical pharmacology at UCLA.

"Of every PET molecular imaging probe that you could identify, about 98% of them are drugs," he said. "The best leads we've got are with therapeutics."

FLT, for example, is an analog of the therapeutic drug azidothymidine. AZT is used to terminate DNA replications, so FLT could help determine at what rate those terminations are occurring. Using the same approach, scientists at UCLA have created an analog of a COX-2 inhibitor to image inflammation, pain, and neurodegenerative diseases. And tracers based on fluorodopa may be useful in imaging Parkinson's disease and some types of cancer.

The majority of tracers being developed focus on cancer and dementia-based diseases such as Alzheimer's disease. Barrio of UCLA has developed FDDNP, an agent that binds to the B-amyloid plaques and tangles in the brain that are features of Alzheimer's disease. Evidence suggests that the molecule binds to the aggregation site of the tangles, which may mean that an analog of the probe could be useful on a therapeutic level.

"There are four million people with Alzheimer's, about 10 million with mild cognitive disorders," Phelps said. "When the baby boomers hit their peak, there will be 12 million of them. If you did a linear extrapolation of the cost right now, it will go from $100 billion to $300 billion. Alzheimer's is a big target for diagnoses and therapeutics."

While tracers that target heart functions will grow in prominence, cancer-specific agents are probably the next big thing in PET, according to Gonzalez.

"We have to keep demographic trends in mind in terms of who are going to be the next users," he said. "Obviously, that's going to be the baby boomers getting prostate cancer or breast cancer. We'll see pressure to develop tracers that are more specific so that the patient will benefit by receiving better treatment."

LONGER LIVED NUCLIDES

Another approach to new tracers comes from looking at longer lived nuclides. Welch and his team at Washington University, along with several other groups, are working on producing compounds using nonstandard PET nuclides. These include copper-64, which has a half-life of 12 hours, bromine-76, with a half-life of 16 hours, and iodine-124, with a half-life of four days.

"Our feeling is that there are PET agents that are easier to distribute throughout the country," Welch said.

These nuclides have been used to label proteins and peptides, along with agents to measure tumor hypoxia and cellular proliferation. Cyclotope is collaborating with Welch's team to produce the tracers, but they are probably years away from general clinical use, due in part to the regulatory environment.

Shorter lived nuclides may also be an option in the future. Smaller cyclotrons that can be used in a clinical setting would enable radiologists to produce the isotopes they need when they need them. Such systems in the clinical setting are currently used almost exclusively to produce FDG.

GE Medical Systems' compact cyclotron, the MiniTrace, can accommodate carbon-11, which is often used in the research environment but not in the clinical setting because of its short half-life of 20 minutes. If clinicians could produce agents based on the short-lived C-11, it could become commercially viable. But the chemistry to produce it, which requires a Ph.D.-level chemist, would first have to be simplified.

Phelps, however, dismisses the idea of incorporating cyclotrons in a clinical setting.

"You want the physician to be the with patient, the scanner, and the imaging," he said. "He or she should not be worried about cyclotrons and synthesizing probes. Real clinical PET works off the clinical pharmacies supplying on a daily basis what they need, and that's fluorine."

POLITICAL CHALLENGES

No matter what emerges from research on possible tracers, the biggest challenge remains one of politics.

"If we don't have an easier regulatory paradigm both at the level of research and at the level of clinical introduction, the field is going to be strangled," Barrio said. "We are not talking about introducing something else in an already saturated medical market in terms of devices and procedures. We are talking about the introduction of new imaging technology that can produce a revolution in the way many diseases are diagnosed and treated."

Patient involvement may make the difference in getting new PET agents approved, according to Welch.

"Part of the reason FDG was approved was political pressure. If research studies show FLT to be of unbelievable benefit in seeing whether major types of cancer therapy are effective, there may be pressure from patient advocate groups that will make the FDA change its position on diagnostic agents. That's the only way it's going to happen," he said.