In Vivo Receptor Assay with Multiple Ligand Concentrations: An Equilibrium Approach

The ligand-receptor binding potential determined by in vivo PET studies at high ligand-specific radioactivity reflects both the receptor density and ligand-receptor affinity. This ambiguity has been resolved by various methods based on the administration of multiple unlabeled ligand concentrations. The authors aimed to implement and refine an approach to multiple ligand concentration receptor assay that combined maximum simplicity and a minimum of assumptions and model dependence that would nonetheless reliably distinguish density from affinity effects. The approach uses administration by bolus followed by infusion to obtain a true equilibrium between bound ligand and the other components of the ligand concentration, and does not require measurements of ligand in blood plasma. Four approaches to the optimization of the desired density and affinity parameters from the measured equilibrium data were implemented and compared in the analysis of raclopride studies performed in both normal control and MPTP-lesioned nonhuman primates. The authors conclude that the method is simple enough for routine use and yet reliable enough to apply in ongoing studies of both chronic and acute drug effects in the dopamine system.

[1]  Bernard Bendriem,et al.  Quantitation of Extrastriatal D2 Receptors Using a Very High-Affinity Ligand (FLB 457) and the Multi-Injection Approach , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  C Crouzel,et al.  Quantification of Benzodiazepine Receptors in Human Brain Using PET, [11C]Flumazenil, and a Single-Experiment Protocol , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  K. Krohn,et al.  Production of [11C]CH3I by single pass reaction of [11C]CH4 with I2. , 1997, Nuclear medicine and biology.

[4]  L. Farde,et al.  Kinetic Analysis of Central [11C]Raclopride Binding to D2-Dopamine Receptors Studied by PET—A Comparison to the Equilibrium Analysis , 1989, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  P. Bédard,et al.  Relation between brain dopamine loss and D2 dopamine receptor density in MPTP monkeys , 1988, Neuroscience Letters.

[6]  Robert B. Innis,et al.  SPECT Quantification of [123I]Iomazenil Binding to Benzodiazepine Receptors in Nonhuman Primates: II. Equilibrium Analysis of Constant Infusion Experiments and Correlation with in vitro Parameters , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  Peter Herscovitch,et al.  Comparison of Bolus and Infusion Methods for Receptor Quantitation: Application to [18F]Cyclofoxy and Positron Emission Tomography , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  Doris J. Doudet,et al.  Effect of Population k2 Values in Graphical Estimation of DV Ratios of Reversible Ligands , 2001 .

[9]  J Delforge,et al.  Absolute Quantification by Positron Emission Tomography of the Endogenous Ligand , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  Richard S. J. Frackowiak,et al.  Striatal D2 receptor status in patients with Parkinson's disease, striatonigral degeneration, and progressive supranuclear palsy, measured with 11C‐raclopride and positron emission tomography , 1992, Annals of neurology.

[11]  W C Eckelman,et al.  Quantification of Amphetamine-Induced Changes in [11C]Raclopride Binding with Continuous Infusion , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

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

[13]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[14]  J. W. Wells,et al.  Dopamine Receptor Parameters Detected by [3H]Spiperone Depend on Tissue Concentration: Analysis and Examples , 1984, Journal of neurochemistry.

[15]  Paul O. Scheibe,et al.  Identifiability Analysis of an In Vivo Receptor-Binding Radiopharmacokinetic System , 1985, IEEE Transactions on Biomedical Engineering.

[16]  P. Larsen,et al.  Synthesis of [11C]iodomethane by iodination of [11C]methane , 1997 .

[17]  A. Gjedde,et al.  Positron emission tomography of radioligand binding in porcine striatum in vivo: Haloperidol inhibition linked to endogenous ligand release , 2000, Synapse.

[18]  J Delforge,et al.  Concept of reaction volume in the in vivo ligand-receptor model. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[19]  M. Laruelle Imaging Synaptic Neurotransmission with in Vivo Binding Competition Techniques: A Critical Review , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  N Satyamurthy,et al.  Regioselective radiofluorodestannylation with [18F]F2 and [18F]CH3COOF: a high yield synthesis of 6-[18F]Fluoro-L-dopa. , 1992, International journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes.

[21]  R J Wyatt,et al.  In vivo PET studies of the dopamine D2 receptors in rhesus monkeys with long‐term MPTP‐induced parkinsonism , 2000, Synapse.

[22]  D. Walters,et al.  Development of Haloperidol‐Induced Dopamine Release in the Rat Striatum Using Intracerebral Dialysis , 1990, Journal of neurochemistry.

[23]  J. Rinne,et al.  Positron emission tomography demonstrates dopamine D2 receptor supersensitivity in the striatum of patients with early Parkinson's disease , 1990, Movement disorders : official journal of the Movement Disorder Society.

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

[25]  M Slifstein,et al.  Effects of statistical noise on graphic analysis of PET neuroreceptor studies. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[26]  Ulla Ruotsalainen,et al.  Increased density of dopamine D2 receptors in the putamen, but not in the caudate nucleus in early Parkinson's disease: a PET study with [11C]raclopride , 1995, Journal of the Neurological Sciences.

[27]  S. Goto,et al.  Subdivisional involvement of nigrostriatal loop in idiopathic parkinson's disease and striatonigral degeneration , 1989, Annals of neurology.

[28]  G Blomqvist,et al.  Comparison of the Transient Equilibrium and Continuous Infusion Method for Quantitative PET Analysis of [11C]Raclopride Binding , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.