Radical Radiopharmaceuticals: Molecular Imaging Agents Find Their Niche

Multiple radiopharmaceuticals in the development pipeline are showing real promise in the realms of oncology, neurology and cardiology. Molecular Imaging Insight visited with three experts who shared some of the radiopharmaceuticals that inspire the most enthusiasm.

Zeroing in on cancer

F-18 fluoroglutamine may hold the most promise in the oncology realm, according to Peter L. Choyke, MD, head of the molecular imaging program at the National Cancer Institute based in Bethesda, Md. The tracer represents a key to diversifying metabolic imaging due to its ability to access a different aspect of energy production involving amino acids, which would provide more detail about tumor physiology and potentially help kickstart a new line of attack

“We’ve developed a lot of targeted drugs against cancer that interrupt various molecular pathways that have had variable success, but almost universally the success is short-lived because cancer cells quickly learn how to bypass the blockage caused by the drug,” says Choyke. To combat this adaptive mechanism, interest is brewing in finding ways to shut down intrinsic pathways within cancer cells, like glycolysis. The process is tricky, because healthy cells need glucose, too. However, by targeting the use of proteins and their metabolites and potentially still other tracers focusing on fatty acid metabolism, it could be possible to get a stranglehold on tumors that simply cannot survive without these essentials.

Another promising area is radiotracers that represent a new arena of disease-specific tumor targeting. One such biomarker is F-18 DCFBC, which banks on the prostate-specific membrane antigen (PSMA), a naturally occurring enzyme present not only in the membranes of primary prostate cells, but in metastatic cells as well. The tracer could be a potentially powerful biomarker for advanced prostate cancer imaging in particular, but it takes years for such investigational agents to break into clinical use.

A different area of avid interest in oncologic imaging is angiogenesis and the proliferation of new cancer cells. FDG is the well-known workhorse revealing areas of increased cellular metabolism, but a newcomer, F-18 39-deoxy-39-fluorothymidine (F-18 FLT), is proving to be not only a contemporary and complement to FDG, but it could one day be a competitor—especially in the context of inflammation and bone marrow imaging.

“F-18 FLT is extremely useful as a partner to FDG, because FDG suffers from some false-positives, especially in the area of inflammation and macrophages that are present in tumors and also pick up FDG. FLT is not burdened by that and as a result will probably characterize a tumor vs. inflammation,” says Choyke. It’s still an experimental agent and, approximately 10 times more expensive than FDG. “Given that, it will probably be reserved for special cases and not routinely used.”

When drugs become the vehicle for validation

Other tumor processes are lighting up for potential tracers. Tumor hypoxia, a lack of oxygen that often signals proliferation or a worsening prognosis as tumors strain against the confines of their environment, has been effectively imaged by F-18 fluoromisonidazole (FMISO)

This agent reports hypoxia and accumulates in the cells of those tumors where oxygen is limited. There are a number of developers working on new drugs that bank on this cellular state. Alone, hypoxia imaging does not seem to be very valuable in changing patient management, but new chemotherapies that are active only in hypoxic cells could alter that substantially. Hypoxia-specific chemotherapies currently in the works would create demand for an imaging agent that highlights the process. Patient selection for these chemotherapies using hypoxia imaging would seem a necessity, but as it stands, there is no guarantee that FMISO will move forward.

“In fact, the drugs utilize the same compound as FMISO to catalyze the reaction that activates the drug,” says Choyke. “That could really be a big boost in the arm if FMISO makes it, and we hope it does.”

To the bone

In terms of bone imaging, F-18 sodium fluoride has been approved for clinical use since 1972 and remains a very high-quality technique for bone cancer and other diseases.

“It has several advantages over conventional Technetium-based bone scanning; it is dramatically more sensitive for metastatic disease,” notes Choyke. In clinical trials where it is important to rule out metastases, F-18 sodium fluoride would be the PET tracer of choice. The tracer also allows clinicians to distinguish degenerative changes in the bone from metastatic disease.

“That is a huge advantage that you generally don’t get in a conventional bone scan,” Choyke continues. “The ability to do that correlation has demonstrated that very subtle changes can be seen on CT that would have been dismissed without the corroboration of the sodium fluoride PET. It’s a very powerful technique, but the jury is still out in terms of general cost effectiveness—whether it’s really worth having this Ferrari of a bone scan or if you could get away with a Ford Focus of a bone scan.”

Looking at logistics

A major limitation of F-18 based agents is that they require a cyclotron to be produced. That sets PET markers conjugated with gallium-68 apart, because these can be procured from a local generator. One such agent, Ga-68 DOTATOC, is making headway in endocrine cancer imaging not only for its efficacy, but its logistical convenience.

“This is an exciting agent,” says Choyke. He estimates that these generators are good for about a year and can be milked for continued product synthesis as needed. “DOTATOC shows great sensitivity and specificity of neuroendocrine tumors greatly surpassing existing methods like octreotide.”

Other tracers that could be translated readily to clinical use include a group of agents indirectly related to tumor hypoxia that home in on carbonic anhydrase IX (CAIX) and pick up on survival mechanisms over-expressed in tumors. One such concept, currently going by the name VM4, is on its way through the approval process. A potential application that has been studied is the differentiation of clear cell and non-clear cell type kidney cancers.

Emerging biomarkers for the brain

Alzheimer’s disease and other neurodegenerative disorders are set to affect as many as 100 million people across the globe by 2050. Neuroimaging is currently one of the most expansive areas of PET imaging and recently saw both U.S. and European approval of Amyvid, a tracer that can image beta-amyloid deposition in the brains of patients with noticeable cognitive decline and symptoms of Alzheimer’s to determine the presence of neurodegenerative pathology. Other tracers that have been more under the radar may soon emerge if promising research continues.

“Because beta-amyloid plaques are the hallmark of Alzheimer’s disease pathology, among others with the tau or neurofibrillary tangles, much effort has gone into developing radiotracers that allow imaging of beta-amyloid plaques in vivo, preferentially at the early stages of the disease,” says Luc Zimmer, PhD, a professor of pharmacology at the University Hospital of Lyon and Lyon Neuroscience Research Center in Lyon, France.

Among the first neurodegenerative disease markers, C-11 PiB has been well studied, but due to its very short half-life of about 20 minutes and the requirement of a cyclotron to produce it, clinical brain imaging with C-11 PiB is hampered. Three F-18 based-agents­—flutemetamol, florbetaben and florbetapir (Amyvid)—have been developed that don’t have these issues.

“Depending on approval by regulatory agencies, these radiotracers are expected to soon become clinically available and provide biomarkers to distinguish patients with Alzheimer’s disease from normal controls and those with other diseases that cause dementia,” says Zimmer. “They also might be used as biomarkers to assess the effect of anti-amyloid therapy, despite several failures for this therapeutic strategy. Finally, alternative targets are currently in development for other neurodegenerative proteins: e.g. tau protein for Alzheimer’s disease or alpha-synuclein for Parkinson’s disease.”

Another marker that continues to develop is F-18 NAV4694, previously named AZD4694. This agent is very similar in chemical structure to C-11 PiB.

Findings from a recent study set F-18 NAV4694 apart from other fluorine-based dementia imaging agents due to its uncanny uptake and low binding to nonspecific white matter nearly identical with C-11 PiB (J Nucl Med. 2013 Jun; 54(6):880-6).

Other areas of interest in metabolic and inflammatory brain imaging include the use of tracers that target the translocator protein (TSPO), a membrane intracellular protein that is over-expressed in inflammatory cells (NeuroImage. 61 (2012) 363–370).

Tracing more of the heart

Meanwhile, researchers are not overlooking the cardiac domain.

An investigational tracer called F-18 flurpiridaz shows a great deal of promise in cardiac imaging, according to Marcelo F. Di Carli, MD, professor of radiology at Harvard Medical School in Boston. F-18 flurpiridaz is currently under development for the evaluation of PET myocardial perfusion and it has some winning qualities, one of which is very high extraction by the myocardium. This allows clinicians to clearly delineate with high sensitivity areas of diseased coronary arteries and more so than other tracers.

“The image quality that has been reported in phase II clinical trials is very impressive as compared to SPECT imaging,” explains Di Carli. “The other issue is that if approved, after phase III clinical trials, this tracer can be distributed on a unit-dose basis so you don’t need to purchase an expensive generator such as with Rubidium-82 or a cyclotron for N-13 ammonia. This tracer would make cardiac PET imaging much more available to a wider range of patients.”

Perfusion is not the only route for detecting cardiac disease. Imaging sympathetic innervation of the heart has been gaining some attention, with one major tracer leading the way: Iodine-123 metaiodobenzylguanidine (I-123 MIBG). A large-scale clinical trial for patients with heart failure demonstrated the tracer’s efficacy in improving patient risk stratification, helping clinicians to predict who has a lower risk of sudden cardiac death and to select patients for defibrillators (JACC. Vol. 55, No. 20, 2010:2212–21).

“This tracer has been approved by the FDA as of April and we will likely see more use of this tracer, which is imaged with SPECT,” says Di Carli. In addition, PET-emitter counterparts similar to MIBG agents are being developed but have a long way to go before they could be approved. Once that happens, these PET alternatives would offer significantly improved image quality and quantitation and not only regional but global sympathetic nerve dysfunction.

Imaging of atherosclerotic plaques is another application where molecular imaging agents are emerging. TSPO may be applicable as the membrane intracellular protein that is over-expressed in inflammatory cells within atherosclerotic plaques, which could potentially tell clinicians about a patient’s level of coronary disease.

“These tracers have been shown in various forms both in preclinical and clinical studies that they may be a better alternative for detecting so called vulnerable plaques compared to FDG,” says Di Carli. “There have been a few publications about these TSPO agents using Carbon-11. The compound that was used was PK-11195. In that publication, the investigators showed that it may offer an improved target to background contrast in terms of detecting atherosclerotic plaques. Newer agents are being developed with fluorine-18, which has a much longer half-life and improved imaging characteristics. Those are potentially promising for looking at vascular inflammation.”

However, Di Carli notes TSPO agents would not have the same value for imaging of the myocardium, as background production of TSPO occurs in normal heart muscle. A tracer along these lines for vascular imaging could reach FDA approval within three to five years, he estimates.

Capturing cardiac remodeling

PET evidence of cardiac remodeling is accumulating in the literature, which stands to bolster the use of a range of predictive biomarkers.

“The most robust papers have used MMP-targeted [matrix metalloproteinase] tracers to evaluate healing after myocardial infarction and predict adverse cardiac remodeling after infarction. Other tracers that have been used for this purpose, but have less validation include tracers assessing angiotensin-converting enzyme activity and tracers targeting inflammation (e.g. FDG) after myocardial infarction,” says Di Carli.

It has not been determined whether these methods will have a significant impact on patient management. Further research will have to be conducted to see if these techniques could be used for patient selection for preventative therapies targeting cardiac remodeling. “[It’s] a very tall order for any of these tracers. Alternatively, these approaches may be useful in drug development and possibly clinical trials.”

At the vanguard of cardiac molecular imaging is the use of nanoparticles for increasingly targeted and finely engineered imaging agents. An example of this is the use of dextran nanoparticles to capture monocyte and macrophage activity in atherosclerotic plagues using both hybrid PET/MR and near infrared imaging (Circ Res. 2013 March 1; 112(5): 755–761).

“Oftentimes, we can’t tell the underlying cause and diagnostic certainty is important,” says Di Carli. “This is an area of clearly unmet need in imaging in general, but it is an area that is quite amenable to molecular imaging.”

Eye on quantification

Cardiac PET studies have shown that myocardial blood flow and coronary flow reserve can fine-tune risk stratification further than conventional cardiac imaging (Circulation. 2011;124:2215-2224).

Currently Ru-82 and N-13 ammonia are approved in the U.S. and have been validated for quantifying both of these cardiac measures and instrumentation. Quantitative software is now more widely available as well. “We are seeing a lot more use of quantitative coronary flow reserve than we were seeing five years ago,” explains Di Carli. “You need tracers that are highly extractable by the heart muscle in order to do that. The only technique that can do it is PET imaging.”

Once approved, F-18 flurpiridaz represents an even more powerful agent for improving the accuracy of these quantitative operations, he continues.
A challenge for all of these and other tracers is that the bar has been raised for gaining regulatory approval, particularly for coronary disease, and it is no easy feat to prove that new tracers will define disease better than existing tracers. This is especially the case for those agents that cost significantly more than conventional methods.

“That is the clear issue with PET imaging,” says Di Carli. “It is unlikely that there will be another tracer approved without demonstrating superiority compared to existing techniques.”