Transient disruption of the blood-brain barrier by intraarterial administration of hyperosmotic agents such as mannitol has been used in humans with brain tumors in an attempt to increase the local delivery of chemotherapeutic agents. Analysis of this approach has been hampered by difficulties in quantifying the delivery of solutes to brain tissue. Techniques using positron emission tomography (PET) are now available to study the underlying physiologic mechanisms. Specifically, the unidirectional transfer rate constant (KI) across tissue capillaries can be determined using Rb-82 administered IV, while local blood flow and blood volume can be measured with other positron-emitting tracers. The short half-lives of these radiotracers permit sequential studies to characterize the physiology and time course of barrier modification in spite of its transient nature, about 30 min. This protocol has two major goals. The first is the development and implementation of specific PET methods to perform the required measurements. We plan to implement the measurement of regional cerebral blood volume with positron-emitting carbon monoxide. In addition, we plan to develop and implement a method for the rapid repeat measurement of regional cerebral blood flow with PET and bolus 0-15 water, at intervals more rapid than the 12 min period now used for sequential flow determinations, i.e. repeat measurements will be made before the radioactive background from the previous measurements has decayed. The second goal of this protocol is to apply these methods along with the use of a third radiotracer, Rb-82 to study the physiology of transient disruption of the blood-brain barrier by intraarterial administration of a hyperosmotic agent, mannitol. These studies will be performed in anesthetized baboons.
