Kinetic Analysis of Central [76Br]Bromolisuride Binding to Dopamine D2 Receptors Studied by PET

The in vivo kinetic analysis of dopamine D 2 receptors was obtained in baboon brain using positron emission tomography (PET) and [ 76 Br]bromolisuride ([ 76 Br]BLIS) as radioligand. An injection of a trace amount of [ 76 Br]BLIS was followed 3 h later by an injection of a mixture of [ 76 Br]BLIS and BLIS in the same syringe (coinjection experiment). A third injection performed at 6 h was either an excess of unlabeled ligand (displacement experiment) or a second coinjection. This protocol allowed us to evaluate in the striatum of each animal and after a single experiment the quantity of available receptors ( B′ max ) and the kinetic parameters including the association and dissociation rate constants ( k +1 V R and k –1 , respectively, where V R is the volume of reaction). The cerebellum data were fitted using a model without specific binding. All the parameters were estimated using nonlinear mathematical models of the ligand-receptor interactions including or not including nonspecific binding. The plasma time-concentration curve was used as an input function after correction for the metabolites. An estimate of standard errors was obtained for each PET study and for each identified parameter using the covariance matrix. The average values of B′ max and K d V R were 73 ± 11 pmol/ml tissue and 1.9 ± 0.9 pmol/ml, respectively. The nonspecific binding was identifiable in the experiment where the last injection corresponded to a second coinjection. We found that ∼6% of the striatal binding was nonspecific after a tracer injection of [ 76 Br]-BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.