Kinetic Analysis of Central [11C]Raclopride Binding to D2-Dopamine Receptors Studied by PET—A Comparison to the Equilibrium Analysis

[11C]Raclopride binding to central D2-dopamine receptors in humans has previously been examined by positron emission tomography (PET). Based on the rapid occurrence of binding equilibrium, a saturation analysis has been developed for the determination of receptor density (Bmax) and affinity (Kd). For analysis of PET measurements obtained with other ligands, a kinetic three-compartment model has been used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equilibrium analysis to data obtained from four PET experiments in each of three healthy subjects. First regional CBV was determined. In the second and third experiment, [11C]-raclopride with high and low specific activity was used. In a fourth experiment, the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concentration of free radioligand and nonspecific binding in brain. Radio-activity in arterial blood was measured using an automated blood sampling system. Bmax and Kd values for [11C]raclopride binding could be determined also with the kinetic analysis. As expected theoretically, those values were similar to those obtained with the equilibrium analysis. In addition, the kinetic analysis allowed separate determination of the association and dissociation rate constants, kon and koff, respectively. Examination of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.

[1]  N. H. Bass,et al.  Cerebral hemodynamics in the rat assessed by a non-diffusible indicator-dilution technique , 1976, Brain Research.

[2]  K. B. Larson,et al.  Strategies for in vivo Measurement of Receptor Binding Using Positron Emission Tomography , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  M. Kuhar,et al.  Dopamine receptor binding in vivo: the feasibility of autoradiographic studies. , 1978, Life sciences.

[4]  C. Bohm,et al.  Automated blood sampling systems for positron emission tomography , 1988 .

[5]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[6]  E. Hoffman,et al.  Tomographic measurement of local cerebral glucose metabolic rate in humans with (F‐18)2‐fluoro‐2‐deoxy‐D‐glucose: Validation of method , 1979, Annals of neurology.

[7]  K. Någren,et al.  Positron emission tomography (PET) in the study of dopamine receptors in the primate brain: evaluation of a kinetic model using 11C‐N‐methyl‐spiperone , 1987, Acta neurologica Scandinavica.

[8]  J. Baron,et al.  In vivo quantitative imaging of dopamine receptors in human brain using positron emission tomography and [76Br]bromospiperone. , 1985, European journal of pharmacology.

[9]  G. Wilkinson,et al.  Perfusion-limited effects of plasma drug binding on hepatic drug extraction , 1976 .

[10]  H Meiners,et al.  [Effects of temperature]. , 1973, ZWR.

[11]  A. P. Hillier.  The rate of triiodothyronine dissociation from binding sites in human plasma. , 1975, Acta endocrinologica.

[12]  T. Walle,et al.  Stereoselective clearance and distribution of intravenous propranolol , 1984, Clinical pharmacology and therapeutics.

[13]  Matts Roos,et al.  MINUIT-a system for function minimization and analysis of the parameter errors and correlations , 1984 .

[14]  J. Olesen,et al.  Isoproterenol and Propranolol: Ability to Cross the Blood-Brain Barrier and Effects on Cerebral Circulation in Man , 1978, Stroke.

[15]  S. Stone-Elander,et al.  No D2 receptor increase in PET study of schizophrenia. , 1987, Archives of general psychiatry.

[16]  J S Fowler,et al.  Kinetic Modeling of Receptor‐Ligand Binding Applied to Positron Emission Tomographic Studies with Neuroleptic Tracers , 1987, Journal of neurochemistry.

[17]  N. Andreasen,et al.  Workshop on schizophrenia, PET, and dopamine D2 receptors in the human neostriatum. , 1988, Schizophrenia bulletin.

[18]  J J DiStefano,et al.  Multiexponential, multicompartmental, and noncompartmental modeling. II. Data analysis and statistical considerations. , 1984, The American journal of physiology.

[19]  E. Hoffman,et al.  TOMOGRAPHIC MEASUREMENT OF LOCAL CEREBRAL GLUCOSE METABOLIC RATE IN HUMANS WITH (F‐18)2‐FLUORO-2‐DEOXY-D‐GLUCOSE: VALIDATION OF METHOD , 1980, Annals of neurology.

[20]  L. Farde,et al.  The new selective D2-dopamine receptor antagonist raclopride--pharmacokinetics, safety and tolerability in healthy males. , 1989, International clinical psychopharmacology.

[21]  W. Pardridge,et al.  Transport of protein-bound hormones into tissues in vivo. , 1981, Endocrine reviews.

[22]  Albert Gjedde,et al.  Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: A re-examination , 1982, Brain Research Reviews.

[23]  D E Kuhl,et al.  Local Cerebral Blood Volume Determined by Three‐Dimensional Reconstruction of Radionuclide Scan Data , 1975, Circulation research.

[24]  H. Akaike.  A new look at the statistical model identification , 1974 .

[25]  J. Links,et al.  Imaging dopamine receptors in the human brain by positron tomography. , 1984, Science.

[26]  G. Schwarz.  Estimating the Dimension of a Model , 1978 .

[27]  G. Sedvall,et al.  Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. , 1986, Science.

[28]  G. Scatchard,et al.  THE ATTRACTIONS OF PROTEINS FOR SMALL MOLECULES AND IONS , 1949 .

[29]  G. Pearlson,et al.  Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. , 1986, Science.

[30]  M. Phelps,et al.  Effects of Temporal Sampling, Glucose Metabolic Rates, and Disruptions of the Blood—Brain Barrier on the FDG Model with and without a Vascular Compartment: Studies in Human Brain Tumors with PET , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  M. Martres,et al.  Widespread distribution of brain dopamine receptors evidenced with [125I]iodosulpride, a highly selective ligand. , 1985, Science.

[32]  S O Ogren,et al.  Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D-2 receptors in the rat brain. , 1985, Biochemical pharmacology.

[33]  S. Kety.  The theory and applications of the exchange of inert gas at the lungs and tissues. , 1951, Pharmacological reviews.

[34]  C. Bohm,et al.  Performance Study of the PC‐384 Positron Camera System for Emission Tomography of the Brain , 1984, Journal of computer assisted tomography.

[35]  G. Sedvall,et al.  Dopamine Receptor Occupancy and Plasma Haloperidol Levels-Reply , 1989 .

[36]  M E Phelps,et al.  Neuroreceptor Assay with Positron Emission Tomography: Equilibrium versus Dynamic Approaches , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[37]  T Greitz,et al.  Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G. Sedvall,et al.  Imaging of neurotransmitter receptors in the living human brain. , 1986, Archives of general psychiatry.

[39]  T. Greitz,et al.  Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. , 1981, Journal of computer assisted tomography.

[40]  H. Thijssen,et al.  Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat. , 1985, Drug metabolism and disposition: the biological fate of chemicals.

[41]  M. Mintun,et al.  A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography , 1984, Annals of neurology.

[42]  D. Craig,et al.  Discriminating interactions between chiral molecules. , 1976, Topics in current chemistry.

[43]  H. Hall,et al.  Effects of temperature on the in vitro binding of 3H-raclopride to rat striatal dopamine-D2 receptors. , 1988, Pharmacology & toxicology.

[44]  Jonathan M. Links,et al.  Imaging dopamine receptors in the human brain by positron tomography , 1983 .

[45]  W. L. Nelson,et al.  The Pharmacokinetics and Pharmacodynamics of d- and dl-Verapamil in Rabbits , 1985, Journal of cardiovascular pharmacology.

[46]  A. Gjedde,et al.  Quantification of Neuroreceptors in the Living Human Brain. I. Irreversible Binding of Ligands , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[47]  P E Roland,et al.  Does mental activity change the oxidative metabolism of the brain? , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.