Future Alternatives to Molybdenum-99 (Mo-99) Production for Medical Imaging

There are current shortages in international supplies of technetium-99m (Tc-99m), the isotope used in more than 80% of diagnostic applications. The investigation into alternatives to Tc-99m has become a top priority. The repeated shutdown of Canada’s aging Chalk River nuclear reactor that produces molybdenum-99 (Mo-99) — from which Tc-99m is derived — and the recent announcement of its permanent closure by 2016, has fuelled the need to find alternative solutions in medical imaging, as has the subsequent cancellation and delay of diagnostic testing throughout Canada and the US. Only five other reactors in the world produce Mo-99 and some of these are experiencing the same age-related problems as the Canadian facility.

Canada produces approximately half the world’s supply of Mo-99¹ and the US imports approximately 50% to 80% of its supply from Canada. The derivative Tc-99m plays an important role in the diagnosis and treatment of conditions such as heart disease and cancer. Tc-99m has a half-life of approximately six hours, so it cannot be inventoried as a precautionary measure when reactors shut down.

Plans to develop alternative solutions that would ensure security of supply were initially halted because two new Canadian reactors were being built as dedicated suppliers of the entire global demand for Mo-99.¹ However, in early 2008, the construction of these reactors was discontinued. At that time, there were no facilities in the US that manufactured commercial quantities of Mo-99.¹

Long-term solutions for the disruption to the continuous and reliable supplies of Tc-99m fall into three broad categories: 

• the building of new, or the modification of existing, nuclear reactors and accelerators to produce medical isotopes
• the development of alternative isotopes that do not rely on existing nuclear reactor and accelerator infrastructures
• a reliance on new and emerging medical imaging devices that bypass the need for Tc-99m.

Table 1 summarizes these technologies and their development status.

1.Investigational technology = one that is either at the conceptual stage, anticipated, or in early stages of development, through to a technology that is undergoing bench or laboratory testing.

Emerging technology = one that is not yet adopted to the health care system, usually in phase II or III clinical trials or pre-launch. The time horizon is 0-5 years before introduction.

Inspired by the ongoing and unscheduled disruption of the supply of medical isotopes, a number of international companies are setting up long-term contingency plans.

In April 2009, MDS Nordion — Canada’s radioisotope production facility — and TRIUMF — Canada’s national laboratory for particle and nuclear physics — announced a collaboration to study commercially viable and reliable supplies of Mo-99 using photo fission-based accelerator technology. More recently, MDS Nordion announced a partnership with the Moscow-based Karpov Institute of Physical Chemistry to supply reactor-based Mo-99.

In June 2009, the Canadian government committed $22 million for infrastructural upgrades to a McMaster University nuclear reactor. The funding will help, in part, to increase Canadian production of medical isotopes. Production at this reactor could begin within 18 months.

Advanced Medical Isotope Corporation (AMIC), a US company, is working in collaboration with a number of universities toward launching compact generator systems and developing and implementing proprietary devices to produce short-lived, as well as longer-lived, isotopes. Over the next two to three years, AMIC plans to produce 13 different isotopes in regional facilities across the US. 

In January 2009, AMIC and the US Department of Energy partnered on a two-year project with the Kharkov Institute of Physics and Technology in the Ukraine to develop and market compact systems technology for producing medical isotopes. 

Also in January 2009, Babcock & Wilcox, an energy technology supplier, signed an agreement with Covidien, a health care products company, to develop solution-based reactor technology for manufacturing Mo-99. Production will use aqueous homogenous reactor technology utilizing low-enriched uranium. This facility could potentially supply 50% of the US market and could be operational by 2012.

In May 2009, Positron Systems and the Idaho State University collaborated to manufacture Mo-99 with proprietary particle accelerator-based technology. Commercial Mo-99 production could start within two to three years at the site.

SNM, an international organization promoting nuclear medicine, recently set up a task force to look at potential domestic supply solutions to medical isotopes in the US. The task force examined the possibility of reviving domestic production of Mo-99 at facilities like the University of Missouri Research Reactor Center in Columbia, Missouri. Production of Mo-99 at this site could begin in 2012 and could potentially meet approximately 50% of the current market demand.

In 2008, URENCO, a manufacturer of enriched uranium, and the Delft University of Technology in the Netherlands collaborated to patent a new technique to produce  Tc-99m that does not require a high neutron influx reactor.

PET scans in Canada

Positron emission tomography or PET is a diagnostic imaging alternative that does not require     Tc-99m. Instead, PET uses isotopes that are produced locally in cyclotrons.  While there are publicly funded PET scanners across Canada, the necessary infrastructure is not currently sufficient for PET to replace the work of Tc-99m isotopes for heart ailments, and cancer diagnosis and staging. In addition, up until  July 2009, PET was only accessible via clinical trials for specific cancers in Ontario or via individually approved access through the Ontario PET Registry Program. Ontario has now made PET scanning a publicly insured health service available to cancer and cardiac patients under  conditions where PET scans have been proven to be clinically effective. The Ontario Ministry of Health and Long-Term Care has also committed a one-time funding of $1.4 million to produce an alternative PET isotope during the current isotope crisis.

As of July 2009, there were 28 centers performing publicly funded scans in seven Canadian provinces. Access to PET scans is greatest in Quebec, with a total of 11 PET/CT (computed tomography) scanners performing clinical scans in the province.  Ontario also has 11 PET/CT which will start performing publicly insured scans in October 2009. Saskatchewan, Prince Edward Island, and Newfoundland and Labrador have no facilities and residents are expected to travel out of province for a PET scan. Newfoundland and Labrador, however, is expected to have a PET/CT scanner in operation within the next three to four years. The status of publically funded Canadian PET scans and cyclotrons  is shown in Table 2.

SPECT and PET hybrids and other molecular imaging solutions

Recent advances in technology have combined PET and single photon emission computed tomography (SPECT) with CT. The main benefit of these combined modalities is increased performance in resolution and sensitivity. 

The development of hybrid imagers originated with PET/CT. While PET alone evolved slowly as an imaging tool relative to other imaging modalities, PET/CT has become the clinically preferred technology for PET imaging. None of the major manufacturers currently offer stand-alone PET scanners for commercial sale.²

Table 2 Location of Publicly Funded PET Scanners and Cyclotrons in Canada (2009)*

Canada has experienced slower uptake of PET. This is believed to be because of the need to more thoroughly evaluate its suitability  for particular clinical applications, given PET’s high capital and operating costs.³ PET/CT is gaining faster acceptance in Canada than stand-alone PET.

The most important application of PET and PET/CT is in oncology;³ this is because whole body imaging is used to identify primary cancer sources and scan for metastatic disease. In comparison, SPECT is more focused on organ function.³

The most important application of SPECT and SPECT/CT is in cardiology. Approximately 60% of SPECT/CT procedures are in this field. However, orthopedics, oncology, and infection imaging are other areas that drive utilization of SPECT/CT.⁴

While PET is a rapidly growing area of nuclear medicine, SPECT still constitutes the majority of nuclear radiologists’ workload; thus, the potential market for SPECT/CT could be larger than that for PET/CT. The equipment and pharmaceutical costs are lower with SPECT and SPECT/CT.⁴

Despite the rapid uptake of hybrid nuclear imaging, there are some drawbacks to the use of CT as a complementary anatomical imaging modality. First, CT exposes patients to ionizing radiation. Second, CT provides relatively poor soft tissue contrast in the absence of oral and intravenous iodinated contrast.² MRI, on the other hand, offers the potential to provide more structural detail than CT scans, especially when imaging soft tissue. MRI does not expose the patient to ionizing radiation,⁵ and it can provide more progressive functionality, such as diffusion and perfusion imaging, as well as spectroscopy.²

PET/MRI technology combines the soft-tissue contrast, high specificity, and structural detail of MRI, together with PET’s sensitivity in assessing physiological and metabolic status.³ It is speculated that technological evolutions of PET/MRI may replace PET/CT as the molecular multimodality imaging platform of choice for cancer, neurologic, central nervous system, and metabolic disorders. In addition, PET/MRI could help verify the efficacy of certain drugs by enabling clinicians to observe how drugs travel through the body.

While the technology required to combine PET/MRI is still in development, PET/MRI will be ready for widespread clinical use within the next decade.⁶ Due to advancements in solid-state gamma camera technology, SPECT/MRI is also on the horizon, but is still in its early stages of clinical development.⁶

D-SPECT is a novel SPECT system for nuclear cardiology. D-SPECT technology allows cross-sectional images of the heart using advanced solid state detectors.⁷ D-SPECT has the potential to offer better energy resolution and higher sensitivity than conventional dual-headed SPECT cameras,⁸ thereby decreasing radiation dose or imaging time, and open the door for the development of entirely new tracers.⁸

Positron Emission Mammography (PEM) — an organ-specific, high resolution PET scanner — is also on the horizon. PEM is affected neither by either breast density or a woman’s hormonal status, two factors that limit the cancer detection effectiveness of both standard mammography and MRI.⁹ This technology is in its infancy, but preliminary reports are promising for the detection of ductal carcinoma in situ (DCIS). No imaging device is currently able to accurately image DCIS, unless it happens to be associated with pleomorphic calcifications seen on mammography. In addition, further refinements, including combining PEM with tomographic acquisition (using rotating detectors), have the potential to improve its diagnostic capabilities compared with the technology based on stationary detectors. While further refinements to the technology are needed, it is believed that its potential to detect early breast cancer is significant.¹⁰

Photo-acoustic imaging

Photo-acoustic imaging is a hybrid imaging modality. A photo-acoustic image is formed by irradiating tissue with pulses of nanosecond laser light, which induces the transient thermoelastic expansion of the tissue. A wideband ultrasonic wave is emitted that can be detected by an ultrasonic receiver. These waves are then converted into high-resolution,  3-D images of tissue structure.

It is believed that photoacoustic imaging may be useful in a number of clinical settings, and could play an important role in the future of mammography as a mass screening alternative to current gold standards.^11,12

Other hybrid imaging technologies

Canada’s Lawson Health Research Institute is currently investigating the plausibility of combining prostate cancer images using CT, MRI, 3-D ultrasound, and nuclear medicine techniques to create a single technological platform to predict the location of cancer within the prostate. This research is intended to advance patient care in prostate cancer diagnosis and it may have applications for many other types of cancer.¹³

The European Institute for Biomedical Imaging Research (EIBIR) is working on a project called ENCITE — the European Network for Cell Imaging and Tracking Expertise. This project is focused on in vivo image guidance for cell therapy and on the development and testing of new MRI imaging methods and biomarkers. Currently, there is no single imaging modality that meets the requirements of cell therapy. It is predicted that these technologies will eventually be used for the treatment of cancer, cardiovascular diseases, and diabetes.¹⁴

There is ongoing interest in developing more easily available and cheaper isotopes. While alternatives to Tc-99m, SPECT’s most important tracer, are sought because of continued disruptions in their supply, alternatives to FDG, PET’s most important tracer, are also in demand because they are expensive and difficult to process.

Clinical trials will soon be completed for two new  I-123-labeled tracer agents. Metaiodobenzylguanidine (I-123 MIBG) is for imaging the sympathetic nervous system of the heart, and p-iodophenyl-3-(R,S)-methylpentadecanoic acid (I-123 BMIPP) for imaging fatty acid metabolism and for use in the emergency department as an evaluation tool for patients who present with episodes of chest pain. The latter tracer, I-123 BMIPP, is marketed as Zemiva^TM and  can directly link symptoms to true cardiac tissue ischemia.¹⁵ The University of Ottawa’s Heart Institute is working on tracer development, while MDS Nordion has helped fund a new lab to focus on early stage characterization of tracers.

MDS Nordion, TRIUMF, and the University of British Columbia recently announced a three-year research and development partnership to develop new diagnostic tracers. The technology will be based on combining select radiometals with newly developed chelates.

There now exists a new positron emission tomography (PET) Fl-18-labeled perfusion tracer, BMS747158. This is a mitochondrial complex 1 inhibitor, which may allow the use of exercise stress ― which, up until now, has not been possible with existing PET perfusion tracers.¹⁶

RAFT-RGD or regioselectively addressable funtionalized template (arginine-glycine-aspartic acid) is another new tracer in development, intended to provide better information about tumour development. It is currently being evaluated for SPECT molecular imaging of new blood supply to tumours. Another new tracer agent for SPECT imaging of the noradrenaline and peripheral benzodiazepine receptors is also in development. This project involves radioiodinated compounds for SPECT imaging of neurological receptors that are implicated in a range of neurological disorders such as clinical depression, Parkinson’s disease, Alzheimer’s disease, anxiety, and stroke.

Thallium-201 is already being used for cardiac perfusion as a replacement SPECT tracer and F-18 fluorine, a PET tracer, is an alternative bone imaging agent to Tc-99m.

While the technologies identified here have the potential for future adoption, it is difficult to determine which products will have any real place in the future. There are a number of determinants that may influence their commercial viability. Even if a technology makes it to launch, there is no certainty that it will command mainstream clinical acceptance; especially if the technology is expensive, is not reimbursable, and is aimed at replacing established modalities where there is already capital, infrastructural, and technological investment. Unanticipated technological developments may also render these technologies obsolete.

Suggested reading:

The development of a PET/CT program in Newfoundland and Labrador. Newfoundland and Labrador Centre for Applied Health Research, 2009: http://www.nlcahr.mun.ca/research/chrsp/EIC_PetCT_full_report.pdf

PET scan primer: A guide to the implementation of positron emission tomography imaging in Ontario. Ontario Health Technology Advisory Committee; 2008: http://www.health.gov.on.ca/english/providers/program/ohtac/pdf/rep_petscan_02_20080925.pdf

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