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

Abstract

Summary:The in vivo kinetic analysis of dopamine D 2 receptors was obtained in baboon brain using positron emission tomography (PET) and C6Brjbromolisuride W6BrjBLlS) as radioligand. An injection of a trace amount of C6BrjBLlS was followed 3 h later by an injec tion of a mixture of C6BrjBLlS and BLIS in the same syringe (coinjection experiment). A third injection per formed 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 avail able receptors (B:naJ and the kinetic parameters includ ing the association and dissociation rate constants (k + I V R and k _ l' respectively, where V R is the volume of reac tion). The cerebellum data were fitted using a model with out specific binding. All the parameters were estimatedThe dopaminergic system was the first neuro transmission system in which it was possible to im age receptors, stored neurotransmitters, and neuro transmitter reuptake mechanisms. For a long time, most researchers endorsed the hypothesis that there were at least two major dopamine receptor types: DJ receptors linked to the stimulation of ade nylate cyclase and D2 receptors linked to the inhi bition of this enzyme (Kebabian and CaIne, 1979 Abbreviations used: BLIS, bromolisuride ; PET, po sitron emission tomography; ROI, region of interest; TLC, thin layer chromatography. 914using nonlinear mathematical models of the ligand receptor interactions including or not including nonspe cific binding. The plasma time-concentration curve was used as an input function after correction for the metab olites. 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:n ax and Kd V R were 73 ± II pmollml tissue and 1.9 ± 0.9 pmollml, 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 C6Brj BLIS. The nonspecific binding appeared to be reversible in the striatum but irreversible in the cerebellum.

Quantitation of Extrastriatal D2 Receptors Using a Very High-Affinity Ligand (FLB 457) and the Multi-Injection Approach

“…The quantity of receptor sites available for in vivo binding, B'max, is very similar in the putamen and the caudate (about 44 ± 13 pmol/mL). This value is very close to the values previously obtained in baboon with bromolisuride using an equilibrium approach, 30 to 40 pmol/mL (Maziere et aI., 1990), but smaller than the value obtained with the same molecule using a multi injection approach, 73 ± II pmollmL (Delforge et a!., 1991). In human, the receptor concentration has been estimated by many groups using raclopride and a Scatchard method (from 28 to 37 pmol/mL [Farde et a!., 1989], from 25 to 44 pmollmL as a function of age [Rinne et aI., 1993], 34.5 pmollmL [Blomqvist et aI., 1990]) or with a kinetics approach (from 22 to 38 pmoll mL [Farde et a!., 1989], 39.6 ± 2.3 [Blomqvist et aI., 1990]).…”

Determination of receptor occupancy in the presence of mass dose: [11C]GSK189254 PET imaging of histamine H3 receptor occupancy by PF-03654746

“…This NTCO correction is suitable for radioligands that are both used at NT dose levels and have a CO effect. For radioligands that are used at NT dose levels, but with sufficiently fast plasma clearance so that no CO effect is detectable, equations (1) to (14) remain valid and can be used for correcting occupancy estimates; however, it would be necessary to perform a study where the mass of radioligand is varied 7,14,21 in order to estimate the radioligand in vivo K d value. In particular, as mentioned above, a controlled saturation study was previously performed to evaluate [ 11 C]GSK189254 in vivo K d value in humans, 7 and the K d value of the present study (9.5 pM) is very similar to that of the saturation study (11 pM).…”

Robust experiment design for estimating myocardial adrenergic receptor concentration using PET

“…[11][12][13][14][15][16][17][18][19][20][21] Moreover, similar PET procedures have also been applied satisfactorily to estimate the concentration of other cellular receptors such as the dopamine and serotonin receptors in the brain. [22][23][24][25] Experiment design considerations: To estimate the receptor concentration distinctly from the receptor-ligand association rate constant, sufficient ligand must be injected into a subject such that it occupies a non-negligible fraction of the receptors. 26 Moreover, a multi-injection protocol may be needed to estimate the receptor concentration uniquely.…”