18FDG for the Study of Central Nervous System Drugs

T first synthesis of 2-Deoxy-2-[F]fluoro-Dglucose (FDG) for human studies took place in 1976, the result of a collaboration between scientists at the National Institutes of Health, the University of Pennsylvania, and Brookhaven National Laboratory, which had begun 3 years earlier. It was developed for the specific purpose of mapping brain glucose metabolism in living humans, thereby serving as a tool in the basic human neurosciences. The FDG method was patterned on the [C]2-deoxyglucose autoradiographic method for mapping regional brain glucose metabolism in animals. With FDG, it was possible for the first time to measure regional glucose metabolism in the living human brain. Later, the utility of FDG for studies of myocardial metabolism and as a tracer for tumor metabolism was reported. Following the first synthesis of FDG via an electrophilic fluorination with [F]fluorine gas (produced via the Ne(d,α)F reaction), small volume enriched water targets were developed that made it possible to produce large quantities of [F]fluoride ion via the O(p,n)F reaction. This was followed by the development of a nucleophilic fluorination method that produced FDG in very high yield. These advances and the remarkable properties of FDG have largely overcome the limitations of the 110-minute half-life of fluorine-18 so that FDG is now available to most regions of the United States from a number of central production sites. This avoids the need for an on-site cyclotron and chemistry laboratory and has opened up the use of FDG to institutions that have a positron-emission tomography scanner (or other imaging device) but no cyclotron or chemistry infrastructure. Currently, FDG is used by many hospitals as an “off-the-shelf” radiopharmaceutical for clinical diagnosis in heart disease, seizure disorders, and oncology, the area of most rapid growth. However, its ready availability has opened the possibility to also use it in drug research and development. This is an important application because with FDG, it is possible to determine which brain regions are most sensitive to the effects of a given drug. Because glucose metabolism reflects, in part, the energy involved in restoration of membrane potentials, regional patterns may be used to generate hypotheses regarding the molecular targets that are mediating the effects of the drug. Also, a baseline study can be run allowing intrasubject comparison before and after the drug. Since subjects are awake and alert at the time of the study, the behavioral and therapeutic effects of the drug and their association with metabolic effects can be measured. Although the use of a functional tracer such as FDG is not as precise as the use of a radiotracer that is more specific for a given neurotransmitter system, it nonetheless provides a measure of the final consequences of the effects of the drug on the human brain. This is important because even though a drug may interact with a particular neurotransmitter, the downstream consequences of that interaction may be of relevance to its pharmacological effects. When radiotracer availability permits, the ideal situation is to pair an FDG measurement with a neurotransmitter-specific measurement and in that way to correlate neurotransmitter-specific effects with regional metabolic effects. This provides a context in which similar approaches may be applied in understanding disease processes and in the development and evaluation of new drug therapies.