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Tracing New Routes
— Taking PET Beyond FDG Researchers are developing new, more specific radiotracers to better target disease at its early stages. Studies on several new tracers designed to treat neurological disorders were discussed at this summer’s Society of Nuclear Medicine meeting. At the Society of Nuclear Medicine’s (SNM) annual meeting in San Diego in June, researchers reported on a number of new radiotracers that will enable them to use PET scans of the brain to help physicians better diagnose neurological disorders and thus enhance the ability to intervene in their progression. Alzheimer’s disease (AD), a progressive, irreversible brain disorder with no known cause or cure impacting approximately 4 million people in the United States, is a prime example. For more than one decade, researchers at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA) have been using a combination of fluorodeoxyglucose (FDG), a glucose radiotracer to demonstrate and measure decrease in the metabolic activity in the brain, and [F-18]FDDNP, a radiotracer labeling the pathological deposits in the brain, for research on early AD diagnosis. Beta-Amyloid By combining the two tracers, the researchers believe, they have developed an extremely accurate way of detecting pathological changes in AD patients’ brains. It is a significant achievement because the clinical methods used to diagnose AD in living patients—cognitive tests to assess symptomatic behavior including memory loss, language impairment, delusions, and dementia—are not definitive. “Proper diagnosis of Alzheimer’s disease can only be made after plaques and tangles have been detected in the brain tissue of patients after they die,” says Vladimir Kepe, PhD, assistant researcher at UCLA who presented the results at SNM. “Having a reliable method for in vivo detection of plaques and tangles would therefore enable us to make the definitive diagnosis while patients are still alive.” Kepe explains that plaques and tangles first appear in one area of the brain and, as the disease progresses, affect increasingly more brain tissue. “In a long preclinical stage, when there are no cognitive symptoms yet present, high densities of tangles and plaques slowly develop in the brain area called the medial temporal lobe,” he says. “As the tangles and plaques develop, so does the cell loss in this region, which eventually leads to short-term memory problems, one of the first signs of AD.” By the time the first symptoms appear, plaques and tangles have also started spreading to the areas of the cortex that are close to the medial temporal lobe, he says. “This eventually leads to brain cell loss in these areas, too, and to worsening of the symptoms. Plaques and tangles continue to spread to other areas of the cortex until the whole brain is affected and behavioral symptoms become severe.” The researchers were able to show that PET scans of the brain with [F-18]FDDNP match this pattern of pathology spreading and progression of AD, Kepe says. In their most recent study, the researchers observed a large group of 83 subjects who underwent PET scans with [F-18]FDDNP. Of the 83 subjects, 25 were AD patients, 28 had mild cognitive impairment (MCI), and 30 were cognitively normal controls. MCI is a class of patients who experience only very mild memory problems but who have a higher probability of developing AD than the control group. The diagnoses of MCI and AD were based on clinical neuropsychological tests, Kepe notes. Distinguishing Between Stages The subjects also received FDG-PET scans and a full set of neuropsychological tests including the Mini-Mental State Exam (MMSE). The researchers found that the FDG results and MMSE scores correlated well with the results from the [F-18]FDDNP scans, Kepe says. Having demonstrated that [F-18]FDDNP PET can distinguish different stages in the pathology of AD, the researchers’ next step is to test whether the radiotracer is capable of detecting the changes in plaque and tangle densities and changes in their distribution pattern in the same patient as his or her disease progresses, Kepe says. Measuring Progression The results, Kepe says, show the tracers’ promise to increase the ability to diagnose AD in its earliest stages, which is essential for successful therapeutic interventions. The goal is to start the therapeutic interventions even before the clinical symptoms become evident when the damage is still localized in the medial temporal lobe—or even earlier—and cell loss is limited, Kepe says. “In this way, we would prevent further cell loss or at least slow it down, effectively stopping the disease in its track.” Kepe says developing therapy for patients who already have advanced disease manifested in cognitive problems is important to prevent further damage, but it cannot restore brain functions that have been lost. At SNM, researchers from the Centre Hospitalier Universitaire (CHRU) Tours in France and the University of Pennsylvania (Penn) in Philadelphia also presented their findings using the new imaging probe IMPY to provide an early diagnosis of AD with SPECT. IMPY was developed by the researchers at Penn to image beta-amyloid plaques in patients with AD. They have been working with researchers at CHRU and Denis Guilloteau, PhD, a biophysics professor and radiopharmacist in the nuclear medicine department, using IMPY to evaluate prion disease. Guilloteau has an animal model that mimics prion disease, says Hank F. Kung, PhD, a professor in the department of radiology at Penn. Prion Diseases In their study, the researchers radioiodinated IMPY to bind to prion deposits in infected mice brain sections. Autoradiography, a procedure where an image is produced on photographic film by the radiation from a radioactive substance, showed a good visualization of these prion deposits, Guilloteau reported. Major accumulations of radioactivity were seen in the cortex, colliculus, hippocampus, thalamus, cerebellum, and pons. The next step is for the researchers to focus on disease progression in animal models in vivo and to correlate the images obtained with clinical symptoms. Researchers at Johns Hopkins University’s (JHU) PET Center in Baltimore have also developed a new radiotracer that can be used to visualize and quantify the brain’s cannabinoid receptors with PET. Their discovery of the [11C]JHU75527 radioligand opens the door for the development of new drugs to treat a host of neurological disorders including drug dependence, obesity, depression, schizophrenia, Parkinson’s disease, and Tourette syndrome. Specific Binding While PET methodology was developed 30 years ago, its application for studying cerebral receptors has been limited due to a lack of suitable radioligands, Horti says. One challenge in developing in vivo CB1 radioligands is finding one that has a high level of specific receptor binding and low nonspecific binding with other proteins, cell membranes, etc. If the nonspecific binding is too high and specific binding too low, the PET images become too “noisy” for quantitative measurements. “Previously developed PET radioligands for imaging CB1 receptors were not suitable for quantitative imaging due to the high level of image ‘noise,’” Horti says. Teaming with world-renowned radiochemists, PET researchers, and nuclear medicine professors, Horti’s group was able, after several years, to develop a PET radiotracer that has a unique combination of good CB1 binding affinity and relatively low nonspecific binding. Studies using mice brains enabled them to select from a series of radioligands a compound that met their criteria. In addition, they studied the effect of non-CB1 central drugs on the uptake of the radiotracer. “Because the non-CB1 drugs did not reduce binding of our radiotracer, we reasoned that the radiotracer binds selectively with CB1 receptors and does not bind with the other central nervous system receptors studied,” Horti says. The mice study required dissection of the mouse brain and assay of the brain regions using a gamma-counter. The researchers then tested the radiotracer that had been selected in the mice experiments on baboon brains. Horti says baboons are a good “rehearsal” for human PET imaging because they are close relatives of humans. The PET images they obtained of the baboon brains demonstrated the regional distribution of radioactivity that matched the known distribution of CB1 receptors. “Our dissection experiments in mice and noninvasive PET studies in baboons confirmed each other,” Horti says. Cannabinoid receptors play an essential role in many central and peripheral disorders. Horti says being able to noninvasively image the central CB1 receptor using PET would provide a great opportunity to study the role of CB1 in various disorders and for the development of cannabinergic medications. Weight Control Safety studies in humans are next on the agenda for the JHU researchers. “The studies include toxicology and radiation safety experiments,” Horti says. “After the completion of the safety studies, we will seek Food and Drug Administration approval for our Investigational New Drug (IND) application.” After obtaining the IND, the group expects to start human imaging. Horti expects the process to take approximately one year. Also at SNM, German researchers reported on their research using PET to demonstrate the beneficial effect of the drug, methylphenidate, on individuals with attention deficit/hyperactivity (ADHD) disorder. Felix M. Mottaghy, MD, PhD, a research fellow at University Ulm in Germany, reported that until their study there had been no direct evidence pointing to the beneficial effect of methylphenidate drugs such as Ritalin on the body’s dopamine system. The University Ulm researchers used PET with 18F-dopa, an imaging drug that is a precursor of dopamine. They were able to show that the brain’s dopamine system is differentially modulated in treated and untreated ADHD patients with respect to healthy normal controls. In a press release, Mottaghy says that “methylphenidate leads to a harmonization of the presynaptic dopaminergic neurons that could explain in part the beneficial effects of this central nervous system stimulant.” The group plans additional studies with more subjects. — Beth W. Orenstein is a freelance medical
writer and regular contributor to Radiology Today.
She writes from her home in Northampton, Pa.
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August
28, 2006
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