The Yale PET Center is experimenting with ways in which positron emission tomography, previously a tool used preferentially for brain imaging studies, can be generalized to study the concentrations of clinically relevant chemical substances in other parts of the body. The center, headed by Professor of Biomedical Engineering Richard Carson, uses an extensive preparation process to identify the target molecule and synthesize an appropriate radioactive tracer to visualize it on the PET scanner. Thanks to the variety and specificity of protein interactions, researchers can use PET to selectively monitor how these substances are altered by the presence of a foreign chemical (such as a pharmaceutical drug) and how they are affected by various diseases.
A full body PET scan using 2-fluorodeoxyglucose.
Copyright SEELA, UCLA
Positron emission tomography works by exploiting one of the properties of antimatter, which consists of particles, such as anti-protons and anti-electrons, which are of the same mass but of opposite charge as those of ordinary matter. Matter and antimatter particles annihilate on contact with one another, producing radiation that can then be measured to determine where the collision took place (1). The tracer, which is injected into the bloodstream before the experiment, has a radioactive isotope and is responsible for emitting the antimatter particles. PET gets its name from the popularity of the radioisotope carbon-11, which is a reliable emitter of anti-electrons, or positrons. When the injection reaches the target site, the tracer binds to its target and begins to radioactively decay. The emitted positrons collide with nearby electrons to produce detectable gamma rays.
Yale’s center is one of the first research labs to combine this traditional PET approach with a pharmaceutical lab, allowing the use of chemical synthesis to design substances that can associate with and visualize virtually any protein in the body. Tracer drug development is highly dependent on both the function of the drug in question and the location of its intended effect. For example, chemicals that target brain cells must have just the right amount of lipophilic character to pass through the blood brain barrier, but not so much that it interferes with binding to their protein targets (2). Other factors like affinity, selectivity, and toxicology also play an important role. These characteristics extend to substances from outside sources. The center has received numerous offers from pharmaceutical companies to test the localization and effects of drugs on various protein systems.
Early testing on neurotransmitter systems in the brain reflects PET’s potential for clinical diagnosis. One study showed that the level of serotonin, a monoamine neurotransmitter that is targeted by numerous drugs (Prozac, Zoloft) that combat depression, was found to correlate positively with the recency of disturbing events in traumatized individuals (3). Another tested neurotransmitter was dopamine, whose concentration in the striatum was positively correlated with activity in the substantia nigra. The death of brain cells in this pathway is responsible for the acute motor impairments seen in individuals with Parkinson’s disease (4).
A later study demonstrated the system’s use in the diagnosis of diabetes. Type I diabetes is caused by a failure in cells of the pancreas to secrete insulin, leading to high levels of glucose in the blood (5). Researchers at the center were able to track insulin by tracking the release of dopamine, which is released in conjunction with insulin. As expected, there was a sharp decrease in the amount of insulin released in individuals with diabetes in comparison to healthy controls. This method can distinguish between Type I and Type II diabetes, as the latter involves deficiency in the cell response to insulin rather than a complete lack of the peptide itself (6). This distinction could make the system a useful tool to physicians in the future.
The Yale PET Center hopes to further refine its efforts by determining a positive marker for Type II diabetes, solving for the small degree of error produced by respiratory movements within the scanner, and experimenting with radiolabeled metabolites.
Sources:
1. L. Campbell, W. L. (1967, April 11). The Ratio of K-capture to Positon Emission in the Decay of 11C. Nuclear Physics A, pp. 279-287
2. Seelig, A., Gottchlichi, R., & Devant, R. (1994, January). A Method to Determine the Ability of Drugs to Diffuse Through the Blood Brain Barrier. Proceedings of the National Academy of Sciences, pp. 68-72.
3. Hirschfield, R. (2000). Sertraline in the Treatment of Anxiety Disorders. Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch.
4. Jankovic, J. (2008). Parkinson’s disease: Clinical Features and Diagnosis. Houston: Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine.
5. Cihakova, D. (2001, September 10). Type 1 Diabetes Mellitus. Retrieved from Johns Hopkins Medical Institutions: http://autoimmune.pathology.jhmi.edu/diseases.cfm?systemID=3&DiseaseID=23
6. Chiu HK, T. E.-W. (2007). Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients. Seattle: Veterans Affairs Puget Sound Health Care System, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington Seattle.