Pictures of the Future    Spring 2007

Nipping Deadly Diseases in the Bud

Dangerous diseases often develop slowly, and can take several years before their first symptoms appear. Long before that happens, however, the body’s metabolism begins to change. With a view to detecting illnesses when metabolic changes begin to occur—and thus improving the probability of successful treatment, experts from a variety of clinical and research fields have been working together for several years to, for instance, identify and detect biomarkers produced by cancers before tumors develop and spread, and to identify the earliest indications of plaques deposits in blood vessels before coronary vessels are compromised. The key to early disease detection is mole­cular medicine, a field that is rapidly gaining in importance due to the evolving convergence of three previously separate fields. These fields are in vitro diagnostics (lab-based analysis of liquids and tissues,  In Vitro Diagnostics), knowledge-based information technology (Knowledge-Based IT) and, above all, in vivo diagnostics imaging.

Two Technologies, One Image. One of the most established molecular imaging technologies is positron emission tomography (PET). Here, a marker such as radioactively tagged sugar 2-deoxy-2[F-18]fluoro-D-glucose (FDG) is injected. Because cancer cells have a higher metabolism than other cells, and thus consume more glucose, the marker tends to accumulate in such cells, which thus light up in a PET image as the marker decays, thus releasing its gamma rays. PET detectors absorb these rays and convert them into weak flashes of light that a computer converts into images. Starting in the mid 1980s, researchers began using PET to track sugar metabolism in the brain. Since the mid-1990s PET has been used clinically to locate primary tumors and metastases and to indicate—depending on tumor size—whether cancer therapies are effective.

But used alone, PET is insufficient because it merely shows the presence of abnormal metabolism without revealing the exact position of the tumor within the body. Anatomical information, the location of internal organs, and even the body’s outlines are often missing from PET images. Considering these limitations, in the late 1990s, Siemens Medical Solutions (Med) developed a device consisting of a PET unit and a computer tomograph (CT). Known as the biograph, the new device was presented at the RSNA 2000. The device directly links PET and CT, which it uses to examine the same body segment (see Hybrid Systems in Pictures of the Future, Fall 2005). The result is an anatomically high-resolution CT image produced in one imaging sweep, which precisely displays a tumor and its metabolic activity (through PET) in its exact position. Such an image makes it easier for surgeons to, for example, plan operations. The combined technology has been dramatically successful. "We now almost exclusively sell PET units with CT functionality," says Dr. Hartwig Newiger, who is responsible for Molecular Imaging Collaborations and Product Support in Europe at Med.

In spite of the biograph’s success, researchers want to achieve more. For instance, they would like to improve the biograph’s operating speed. They are also working on more efficient algorithms in order to improve contrast resolution and recognition of specific details. Such algorithms are important "because the resolution of whole-body PET systems is physically limited to two to four millimeters," says Newiger. That level of resolution has more or less already been achieved. Because of these limitations, small structures may appear as larger spots in PET images. But thanks to CT, with its resolution of up to 150 µm, fine substructures and their relationship to surrounding tissues can be exactly visualized.

A Picture of Alzheimer’s. Furthermore, medical specialists want to be able to make more precise statements regarding certain metabolic processes that cannot be identified with FDG. Med is therefore working with renowned research institutes around the world to develop new marker substances that will be able to pinpoint and make visible even very small metastases and individual tumors, while at the same time identifying the type of tumor in question.

In 2005, following years of collaborative development work, Siemens acquired CTI Molecular Imaging, Inc., one of the world’s leading manufacturers of PET devices and PET marker substances. Experts from the resulting hybrid organization—Siemens Medical Solutions Molecular Imaging (MI)—are now developing technologies that make the most of recent hardware developments to better visualize new, radioactively-tagged biomarkers.

Siemens is also working closely with independent molecular imaging specialists such as Prof. Michael Phelps from the Department of Molecular and Medical Pharmacology at the University of California in Los Angeles, and Prof. Ralph Weissleder, Director of the Center for Molecular Imaging Research at Massachusetts General Hospital in Boston (see  Interview with Prof. Weissleder). In the December 2006 issue of the renowned New England Journal of Medicine, scientists working with Phelps reported on a new Alzheimer’s marker developed in cooperation with Siemens.

Siemens holds an exclusive license for the new marker, which binds specifically with proteins called amyloid plaques that build up in the brains of Alzheimer’s patients. When tagged with a short-lived radioactive substance, the markers can be clearly visualized in PET scans, thus indicating damaged areas (picture). Thanks to this evolving technology, patients suspected of having Alzheimer’s can be clearly distinguished from patients with other types of dementia and from healthy subjects, thus opening the door to future targeted treatments. Researchers believe that such markers will make it possible in the future to identify Alzheimer’s several years before the onset of symptoms.

Understanding Metabolism. Ralph Weissleder has been working with Siemens since 2003. He is involved in the development of markers and pre­clinical contrast media for testing with animals, and also works on integrating different imaging technologies, such as magnetic resonance tomography (MR) and iron nanoparticles. Weissleder believes that molecular imaging is one of the most promising research areas in medicine today, offering the potential not only of early identification of many diseases, but also of improved diagnostic and therapeutic accuracy. "Molecular imaging can help to significantly reduce unnecessary treatments and surgery," Weissleder explains. What’s more, he points out that in the future, fluorescent probes will be available that will be able to zero in on cancer cells, allowing surgeons to detect and eliminate cancer cells that might otherwise have been left behind, thus significantly improving the probability of long-term recovery.

With an eye on the vast field of biomarkers, Siemens is expanding its mole­cular imaging R&D center in Los Angeles. The center has already received FDA approval to start clinical trials on a new imaging biomarker for Alzheimer’s disease. One of the challenges in developing new biomarkers is how to gain an understanding of underlying metabolic processes in order to identify substances that will bind to key elements of such processes. Such substances can then be synthesized with the help of specific chemical reactions (click chemistry), after which they can be marked with a radioactive isotope. FL-thymidine (FLT) is a very promising new biomarker candidate that is now being studied by Siemens researchers. FLT penetrates into the interior of a cell and works at the molecular level. The FLT molecule is similar to thymidine, one of the building blocks of DNA. It accumulates particularly in those areas where DNA is produced in large quantities, in other words, in tumors. FLT is also better than FDG at identifying cell growth and distinguishing it from infections.

Fluorine-18 (¹⁸F) is a key isotope used in conjunction with PET scanning. But like other PET isotopes, it requires the use of particle accelerator (cyclotron) to produce it—devices that are beyond the capabilities of many hospitals. With this in mind, Siemens has spent years building up an order and supply network for PET isotopes. Known as PETNET, the network is well established in the United States, the UK and South Korea. Naturally, Siemens also sells cyclotrons to hospitals and laboratories. These units from Siemens’ Eclipse product family are connected to Explora biomarker production machines, which automatically attach the isotope generated in the cyclotron to a carrier substance. Radioactive markers are also used with another imaging method known as single photon emission computed tomography, or SPECT. The advantage of such markers is that they do not require a cyclotron for their production, as the radioactive isotope most frequently used with SPECT—technetium-99m (^99mTc)—can be produced with a relatively small "generator."

^{Pre-clinical research. CT (left, center) and PET/CT are used for imaging mice. The results can reveal the precise progress of tumor growth and the destruction of bones (right)}

Research on Animal Models. New markers and molecular imaging technologies require preclinical research. That’s why Med also focuses on the development of imaging techniques that are tailored for use with rodents and primates. These methods make it possible to monitor the course a disease takes in an animal over a long period, enabling new and even more specific marker substances to be tested and later used in human patients. Use of these imaging techniques does not mean that animals must be killed in order to gain detailed information regarding their physiological processes. On the contrary, MI makes it possible to study test animals, which may represent years of research, over extended periods of time in order to determine the effect of medications and the course of therapy.

Until recently, Siemens supplied separate "microPET" and "microCAT" devices for PET and CT examinations of animals. However, as has already occurred with respect to human medical applications, these devices have been merged into a single, combined machine known as "Inveon." Depending on a research project’s requirements, animal PET and CT capabilities can now be linked, and even supplemented by a SPECT unit.

Such flexibility makes it possible to choose the best imaging technique for the examination in question. The advantage offered by Siemens PET scanners is that they use a unique, ultra-sensitive detector material developed and manufactured by MI in Knoxville that efficiently transforms extremely weak radiation into visible light, which in turn results in images that enable scientists to precisely observe the effects that substances under study have on test animals.

Increasingly sensitive detectors even make it possible to view the interaction between immune cells and their target organs (lymph nodes, thymus), or the activities of animal brain receptors, in real time. Inveon SPECT delivers even better spatial resolution, albeit with lower sensitivity than PET. This drawback is partially offset, however, by the fact that SPECT examinations do not require cyclotrons. The CT portion of a scan, for its part, provides precise anatomical information for measuring bone density during osteoporosis examinations, for example. Depending on the type of study in question, medical researchers can use any combination of SPECT, CT and PET from a work station. They can even conduct scans utilizing all three procedures, which in turn enables several parameters to be studied simultaneously.

Pinpointing Effective Medications. In vivo diagnostics and devices such as Inveon are suitable for diverse preclinical research applications, "because many basic biochemical processes in humans and mice are very similar," explains Dr. Antje Schulte, who is responsible for Product Support at Med in Erlangen. Among the phenomena studied are brain structures that give rise to Alzheimer’s disease, receptors for addictive drugs and the effectiveness of new cancer medications. "In the past, PET, SPECT and CT were mostly used by research institutes as basic research tools; today, more and more pharma­ceutical companies are employing the devices for product-related research purposes," explains Schulte. Pharmaceutical companies also want to find out if a substance is suitable for use as a medication, or if it would be better to abandon it immediately. That’s because the sooner a substance can be excluded, the more money can be made available for the study of more promising candidates.

Revolutionary Combination. Siemens works closely with external experts in order to ensure that its medical equipment and related software meets the practical requirements of its customers. One such expert is Dr. Bernd Pichler from the University of Tübingen, Germany, who was responsible for setting up Siemens’ European Training and Reference Lab at Tübingen. The lab specializes in training new users in small animal imaging as well as in assessing new devices to determine their suitability for everyday use—microCAT, microPET and Inveon are among the machines it has tested.

Molecular imaging is one focus of Pichler’s work, and with it he has examined phenomena such as oxygen-starved tumors, which are known as hypoxic tumors. "Remarkably, tissue areas subject to poor circulation like these are especially resistant to radiation treatment and chemotherapy," says Pichler. The goal here is to locate hypoxic areas using specific markers so as to be able to combat tumors with a more targeted approach. Such an approach would also ensure that healthy tissues, and the patient’s body as a whole, would be exposed to the least possible amount of medical treatment. With this in mind, Siemens, together with Pichler, is currently developing entirely new, combined devices for small animal imaging that will put MR and PET scanning into a single device.

In addition to visualizing soft tissues, MR can be used for imaging the circulatory system when employed in conjunction with a contrast medium. This can, among other things, facilitate identification of otherwise hard-to-detect hypoxic tumors. Considering these benefits, Siemens and the University of Tübingen plan to begin testing a prototype MR/PET scanner this Spring that will be used exclusively for studies of the human brain.

MR is also becoming more and more important in molecular imaging. "The great thing about MR is that it can be used to pinpoint disease markers," says Dr. Robert Krieg, head of Molecular MRI at Med in Erlangen. For instance, a patient can be injected with a contrast medium that is designed to accumulate only in tumor tissue, while producing a clear signal that is captured in an MR image. New types of contrast media are much more specific, however, because they deliver images of the patient’s entire anatomy as well as the target tissue’s physiological activity after just one sweep of the body by the imaging device. Known as mMRI (molecular Magnetic Resonance Imaging), the development of specific molecular markers is expected to open up a range of new diagnostic and therapeutic possibilities. "However," cautions Dr. Arne Hengerer, mMRI project manager at Med, "It will definitely take at least eight years for the first mMRI markers to reach the market."

Iron Nanoparticles. There are already several promising approaches. For example, an mMRI marker consisting of an iron nanoparticle that’s absorbed by macrophages is now being clinically tested. Macrophages are immune cells found primarily in lymph nodes. But if a node harbors cancer cells, the number of immune cells in it declines. Thus, if injected nanoparticles fail to be absorbed by a lymph node, it is an indication of metastatic cancer, since cancers spread primarily via the lymph nodes.

Another mMRI contrast medium is being developed by Nano AG, a consortium led by Siemens’ Hengerer. Nano AG is working closely with Charité Hospital, Ferropharm, Schering and Mevis, the University of Freiburg, and the German Cancer Research Center in Heidelberg. The consortium’s project is also being funded by the German Ministry of Education and Research. Under development is a new medium that contains iron oxide nanoparticles designed to specifically home in on so-called "vulnerable plaques" in blood vessels. These plaques deposits are unstable and thus capable of triggering clotting that can suddenly block a vessel, resulting in heart attack or stroke.

If doctors could recognize vulnerable plaques at an early stage and distinguish such deposits from relatively harmless stable plaques, patients could be treated with special medications and might be able to avoid life-threatening clotting incidents. And that’s precisely the goal set by Nano AG. In view of such possibilities, Robert Krieg believes that the future belongs to mMRI. Iron oxide contrast media now being studied already indicate just how valuable the combination of advanced imaging and targeted contrast media promises to be in terms of under- standing disease pathology, accurately diagnosing conditions, and ultimately developing treatments that stop diseases before they pose a life-threatening risk. Thanks to all of this, it may indeed one day be possible to nip deadly diseases in the bud.
                                                                                                                    Tim Schröder