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A new imaging method could show how cannabinoids affect diseases like schizophrenia.
Scientists have long known that the brain possesses natural chemicals similar to marijuana. While little is known about their precise function in the brain, studies suggest that these compounds, known as cannabinoids, and the receptors they bind to, play a role in diseases, including schizophrenia, Parkinson's disease, and obesity.
Now researchers at Johns Hopkins University have developed a way to image cannabinoid receptors in living animals. The tool will help scientists figure out how these receptors are altered in drug addiction and disease, as well as helping pharmaceutical companies to design drugs that better target this system.
"This is a real breakthrough," says Richard Frank, vice president of medical affairs at GE Healthcare in Princeton, NJ. "Scientists have long believed that the cannabinoid system is involved in diseases, but they've never been able to measure the receptor in living people's brains." The new tracer acts as a receptor antagonist -- meaning it blocks the receptor but does not activate it. That's important, says Frank, because the compound has no pharmacologic effect. In other words, it doesn't make the user feel "high."
Andrew Horti and Robert Dannals at Johns Hopkins designed a novel compound that selectively binds to the cannabinoid receptor, CB1, in the human brain, and labeled it with a radioactive tag. They then used imaging technology known as positron emission tomography (PET) to determine precisely where in the brain the receptors were present. "Such tracers offer the opportunity to study if receptors in the brain are static or if they increase or decrease when we're exposed to different substances [such as marijuana]," says Dannals, senior author on the study, whose results were presented at the Society of Nuclear Medicine meeting in San Diego last week. Such studies could give clues to addiction or other disorders.
Other such tracers exist for a myriad of brain receptors, including ones for opiates and serotonin, a neurotransmitter involved in depression. But creating an analogous molecule for cannabinoid receptors has been a challenge. Tracers are injected into a patient's bloodstream, where they travel to the brain and compete with naturally occurring chemicals for binding sites on the target receptors. But cannabinoid-like molecules are fat-soluble, meaning they're attracted to the lipid membranes of cells, and have trouble crossing the blood-brain barrier. (THC, the main active compound in marijuana, is an exception.) But Horti was able to design a molecule that could cross the blood-brain barrier and was highly specific to the CB1 receptor.
Scientists will also be able to study disorders that have been linked to the cannabinoid system, such as schizophrenia and Parkinson's disease. For example, smoking marijuana appears to precipitate symptoms of schizophrenia. Furthermore, schizophrenics seem to have higher levels of cannabinoids in their brains. But animal studies of these diseases have produced conflicting results, says Andrea Giuffrida, a neuroscientist at the University of Texas Health Science Center in San Antonio. The new imaging method, he says, "will be useful to understand exactly what's going on."
The same is true for Parkinson's disease. Some scientists speculate that cannabinoids play a protective role in the brain, slowing the rate of disease. But knowing exactly what happens to patients as the disease progresses is crucial, says Giuffrida.
The new tracer could also aid in drug development. Marijuana is already used to help cancer and AIDS patients with chronic pain or nausea. But many of these patients would prefer a version of the drug that comes without the mood-altering high. "[The tracer] may help us design the next generation of cannabinoid-based medicines -- for example, chemicals that boost the activity of brain marijuana-like compounds without directly activating cannabinoid receptors," says Daniele Piomelli, director of the Center for Drug Discovery at the University of California, Irvine.
Paris-based drug maker Sanofi-Aventis has already developed an anti-obesity drug that blocks cannabinoid receptors. The drug, which is expected to gain Food and Drug Administration approval within the next few months, will be the first cannabinoid blocker in use. Such PET tracers could help drug designers by giving them a direct way to measure how well an experimental compound binds to its target.
The new tracer will also help scientists learn more about marijuana addiction, and possibly treat it more effectively, says Henry Wagner, director of the division of radiation health sciences at Johns Hopkins University (who was not involved in the research). With the new tracer, neuroscientists could determine if smoking marijuana increases the number of cannabinoid receptors in the brain, which could lead to a craving for more of the drug.
Horti and colleagues have tested the tracer in rodents and baboons and confirmed that the compound accurately portrays the distribution of receptors, as shown by post-mortem studies. They're now conducting safety studies, required by the FDA for using the compound in humans, which they estimate will be complete in three to six months.
Scientists have long known that the brain possesses natural chemicals similar to marijuana. While little is known about their precise function in the brain, studies suggest that these compounds, known as cannabinoids, and the receptors they bind to, play a role in diseases, including schizophrenia, Parkinson's disease, and obesity.
Now researchers at Johns Hopkins University have developed a way to image cannabinoid receptors in living animals. The tool will help scientists figure out how these receptors are altered in drug addiction and disease, as well as helping pharmaceutical companies to design drugs that better target this system.
"This is a real breakthrough," says Richard Frank, vice president of medical affairs at GE Healthcare in Princeton, NJ. "Scientists have long believed that the cannabinoid system is involved in diseases, but they've never been able to measure the receptor in living people's brains." The new tracer acts as a receptor antagonist -- meaning it blocks the receptor but does not activate it. That's important, says Frank, because the compound has no pharmacologic effect. In other words, it doesn't make the user feel "high."
Andrew Horti and Robert Dannals at Johns Hopkins designed a novel compound that selectively binds to the cannabinoid receptor, CB1, in the human brain, and labeled it with a radioactive tag. They then used imaging technology known as positron emission tomography (PET) to determine precisely where in the brain the receptors were present. "Such tracers offer the opportunity to study if receptors in the brain are static or if they increase or decrease when we're exposed to different substances [such as marijuana]," says Dannals, senior author on the study, whose results were presented at the Society of Nuclear Medicine meeting in San Diego last week. Such studies could give clues to addiction or other disorders.
Other such tracers exist for a myriad of brain receptors, including ones for opiates and serotonin, a neurotransmitter involved in depression. But creating an analogous molecule for cannabinoid receptors has been a challenge. Tracers are injected into a patient's bloodstream, where they travel to the brain and compete with naturally occurring chemicals for binding sites on the target receptors. But cannabinoid-like molecules are fat-soluble, meaning they're attracted to the lipid membranes of cells, and have trouble crossing the blood-brain barrier. (THC, the main active compound in marijuana, is an exception.) But Horti was able to design a molecule that could cross the blood-brain barrier and was highly specific to the CB1 receptor.
Scientists will also be able to study disorders that have been linked to the cannabinoid system, such as schizophrenia and Parkinson's disease. For example, smoking marijuana appears to precipitate symptoms of schizophrenia. Furthermore, schizophrenics seem to have higher levels of cannabinoids in their brains. But animal studies of these diseases have produced conflicting results, says Andrea Giuffrida, a neuroscientist at the University of Texas Health Science Center in San Antonio. The new imaging method, he says, "will be useful to understand exactly what's going on."
The same is true for Parkinson's disease. Some scientists speculate that cannabinoids play a protective role in the brain, slowing the rate of disease. But knowing exactly what happens to patients as the disease progresses is crucial, says Giuffrida.
The new tracer could also aid in drug development. Marijuana is already used to help cancer and AIDS patients with chronic pain or nausea. But many of these patients would prefer a version of the drug that comes without the mood-altering high. "[The tracer] may help us design the next generation of cannabinoid-based medicines -- for example, chemicals that boost the activity of brain marijuana-like compounds without directly activating cannabinoid receptors," says Daniele Piomelli, director of the Center for Drug Discovery at the University of California, Irvine.
Paris-based drug maker Sanofi-Aventis has already developed an anti-obesity drug that blocks cannabinoid receptors. The drug, which is expected to gain Food and Drug Administration approval within the next few months, will be the first cannabinoid blocker in use. Such PET tracers could help drug designers by giving them a direct way to measure how well an experimental compound binds to its target.
The new tracer will also help scientists learn more about marijuana addiction, and possibly treat it more effectively, says Henry Wagner, director of the division of radiation health sciences at Johns Hopkins University (who was not involved in the research). With the new tracer, neuroscientists could determine if smoking marijuana increases the number of cannabinoid receptors in the brain, which could lead to a craving for more of the drug.
Horti and colleagues have tested the tracer in rodents and baboons and confirmed that the compound accurately portrays the distribution of receptors, as shown by post-mortem studies. They're now conducting safety studies, required by the FDA for using the compound in humans, which they estimate will be complete in three to six months.
