The in Vivo Determination of Lig and Binding Within the Central Nervous System (Muscarinic Receptor, Emission Tomography, Autoradiography).

The distribution of diffusible radiotracers in the brain is considered with the goal of determining regional properties of neurotransmitter binding sites in vivo. Quantification of receptor binding is dependent on selection of an appropriate lig and and on development of a compartmental model describing in vivo lig and distribution. Tracer selection criteria identified include: availability of a radiochemical synthesis; predicted blood-brain barrier permeability; specificity, affinity and kinetics of the receptor-lig and interaction; and metabolism of the lig and . A compartmental model is developed in which the brain contains free, nonspecifically bound and specifically bound tracer. It is assumed that free tracer exchanges between tissue and intravascular pools. The model is tested by analysis of equilibrium and kinetic tracer distribution experiments with the use of {('3)H}scopolamine to label the muscarinic cholinergic receptor in the rat brain. In equilibrium experiments following administration of scopolamine (0.6 umol/kg), specific binding demonstrates saturability, an affinity relative to other drugs, and regional binding capacities which are consistent with the known properties of muscarinic receptors. In vivo estimates of receptor density are highly correlated with in vitro measurements, and are greatest in the striatum, intermediate in the neocortex and hippocampus, and low in the cerebellum. Kinetic analysis of trace binding conditions following injection of 6 nmol/kg of scopolamine permits estimation of the blood-brain barrier permeability and nonspecific binding of the lig and . While kinetically determined regional estimates of free receptor density are in general agreement with the rank order of binding capacities measured in the equilibrium studies, the cortex has a greater apparent density of free receptors than does the striatum. It is suggested that this reversal in the rank order of binding capacities and free receptor densities reflects differential receptor occupancy by endogenous neurotransmitter. The model developed in this work is generally relevant to the in vivo study of lig and binding sites. This approach is applicable to quantitative receptor imaging in humans by positron or single-photon emission tomography.PhDAnimal PhysiologyUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160310/1/8502812.pd