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Brain Receptor Imaging Wolf-Dieter Heiss, MD and Karl Herholz, MD

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  • 1. Brain Receptor Imaging Wolf-Dieter Heiss, MD and Karl Herholz, MD Journal of Nuclear Medicine Vol. 47 No. 2 302-312 報告者 / Int 劉珈倩
  • 2. Introduction
    • Receptors are structures, usually proteins, on cellular membranes
      • Interaction with specific ligands (first messenger transmitters)
      • Trigger a signal causing defined responses
        • Secondary messengers (G-protein–coupled receptors)
        • ion channels (ligand-gated ion channels)
  • 3. Introduction
    • Receptors involved in direct neurotransmitter function are found in high density in specific brain areas.
      • They form a primary target for imaging studies.
    • Other receptors have a modulating effect on signal transduction.
      • They distributed in lower density and their in vivo detection is still limited but might gain importance in the future.
  • 4. Introduction
    • Distribution, density, and activity of receptors in the brain can be visualized and quantified by radioligands .
      • Must fulfill criteria for PET or SPECT
  • 5.  
  • 6. IMAGING AND QUANTITATIVE ANALYSIS OF RADIOLIGAND STUDIES
  • 7. Imaging And Quantitative Analysis
    • PET
      • represents the most selective and sensitive (pico- to nanomolar range) method for measuring receptor density and interactions in vivo.
    • SPECT
      • can also be applied but detector efficiency is much lower and it provides less quantitative accuracy than PET
  • 8. Imaging And Quantitative Analysis
    • Kinetic studies are necessary
      • Differentiate the various components
      • Extract the compartment of specific binding.
  • 9. DETERMINATION OF RECEPTOR BINDING
  • 10. Determination of receptor binding
    • 3-compartmental model
      • Free exchangeable ligand in plasma,
      • The free-to-bind ligand in tissue,
      • The specifically bound ligand forming the compartments
  • 11.  
  • 12. Determination of receptor binding
    • Differential equations describe the change of concentrations in these compartments over time:
  • 13. Determination of receptor binding
    • The proportion of labeled tracer to total amount of injected ligand must also be considered in the equations:
  • 14. Determination of receptor binding
  • 15. RADIOLIGANDS FOR NEURO RECEPTOR IMAGING BY PET AND SPECT
    • For SPECT, most of the ligands tested in humans were labeled with 123 I.
    • For PET , the ligands applied in humans were usually labeled with 11 C or 18 F
  • 16. DOPAMINE SYSTEM
  • 17. Dopamine System
    • Proper movement coordination,
    • Degeneration of the nigrostriatal dopamine system causes Parkinson's disease
    • Pulsatile dopamine secretions
      • pleasant feeling
      • a strong reward system that appears to play also a central role in drug abuse.
  • 18. Dopamine System
    • 2 major dopamine receptor types
      • D 1 and D 2 ;
      • Have been imaged in humans
    • 3 other types
      • D 3 , D 4 , and D 5
        • D 3 and D 4 are close to D 2
        • D 5 is close to D 1 .
  • 19. Dopamine System
    • Labeled benzazepines
      • Potent and selective D 1 antagonists.
      • D 1 receptor tracers (11C-SCH 23390, 11C-NN112 ),
        • PET ( striatum > kinetic regions = neocortex > thalamus),
        • An age-dependent decrease (7% per decade) was observed.
    D 1
  • 20. Dopamine System
        • Significant decrease in D 1 receptor density in the
          • Bipolar affective disorders
            • striatum and frontal cortex
          • Schizophrenia.
            • prefrontal cortex
          • These tracers were also applied in competition studies to examine the binding of neuroleptic drugs to D 1 receptors and for studies in Parkinson's disease
    D 1
  • 21. Dopamine System
    • Benzamide 11 C-raclopride
      • gold standard PET tracer for D 2 receptors
      • has a medium affinity to D 2 receptors (Kd, 1.2 nmol/L), is displaced more easily, and does not bind to 5-HT receptors.
    • 123 I-iodobenzamide
      • the most widely used D 2 receptor tracer for SPECT .
    D 2
  • 22. Dopamine System
    • Benzamide derivatives
      • with picomolar affinity
        • suitable for investigation of extrastriatal D 2 receptors.
      • binding capacity is measured after equilibrium with plasma levels has been reached
        • suitable to study receptor occupancy by neuroleptics or altered dopamine release.
    D 2
  • 23. Dopamine System
    • In idiopathic Parkinson's disease
      • The binding capacity of striatal D 2 receptors is increased,
      • Decrease in 18F-DOPA uptake ,
      • After transplantation of medullar or fetal mesencephalic grafts to the putamen of patients with Parkinson's disease, no postoperative alteration of receptor density was observed despite some clinical improvements and increase in 6-fluoro-L-DOPA (FDOPA) uptake
    D 2
  • 24. Dopamine System
    • In progressive supranuclear palsy
            • Parkinsonian syndrome caused by multisystem atrophy,
      • A loss of striatal D 2 receptors,
      • This loss of receptors was accompanied by a significant decrease in 18F-labeled 3,4-dihydroxyphenylalanine (18F-DOPA) uptake ,
        • both pre- and postsynaptic neuronal degeneration.
    D 2
  • 25.  
  • 26. SEROTONIN (5-HYDROXYTRYPTAMINE, 5-HT) SYSTEM
  • 27. Serotonin System
    • Serotonergic neurotransmission is altered in many neurologic and psychiatric disorders
      • In depression and compulsive disorders
      • Alzheimer's and Parkinson's disease, autism, and schizophrenia.
  • 28. Serotonin System
    • There is a great heterogeneity of the postsynaptic 5-HT receptors.
      • 7 major classes
      • >16 subtypes .
    • Suitable radioligands are only available for 5-HT 1A and 5-HT 2A receptors.
  • 29. Serotonin System
  • 30. Serotonin System
    • 5-HT 2A receptors are present in all neocortical regions
      • with lower densities in hippocampus, basal ganglia, and thalamus
    • Reduced 5-HT 2A receptor binding may be related to the pathophysiology of anorexia nervosa.
  • 31. Serotonin System
    • Interest in 5-HTT is based on the essential role of the 5-HT system in depression.
      • tricyclic and nontricyclic antidepressants
        • inhibitors of 5-HT reuptake, which enhance extracellular 5-HT levels.
    • Many antidepressants were labeled
      • high lipophilicity -> high nonspecific binding.
  • 32. CHOLINERGIC SYSTEM
  • 33. Cholinergic System
    • Nicotinic receptors
      • belong to the ligand-gated ion channels.
    • Muscarinic receptors
      • operate via several second messengers
  • 34. Cholinergic System
    • Nicotinic receptors
      • Depression
      • Cognitive and memory disorders
        • Alzheimer's and Parkinson's disease.
      • 11 C-labeled nicotine .
        • High binding was reported in several cortical and subcortical regions,
          • thalamus and hypothalamus or midbrain
  • 35. 11 C-MP4A PET
    • Early in the course of Alzheimer's disease, a reduced uptake of radioligands to nicotinic receptors in frontal and temporal cortex
    • Reduction in cortex and amygdala but preserved activity in basal forebrain
  • 36. Cholinergic System
    • Muscarinic receptors
      • Dominant postsynaptic cholinergic receptors
        • Many tracers for SPECT and PET
          • Lack selectivity for receptor subtypes.
      • Parkinson's disease
        • Hypersensitivity of muscarinic receptors
          • in the frontal cortex .
  • 37. γ -AMINOBUTYRIC ACID (GABA) SYSTEM
  • 38. γ -Aminobutyric Acid (GABA) System
    • GABA : The most important inhibitory neurotransmitter
      • Epilepsy
      • Psychiatric disorders
      • Anxiety
    • GABA receptor
      • Very sensitive to damage
      • A reliable marker of neuronal integrity
        • In ischemic brain damage
        • In various neurodegenerative diseases.
  • 39. γ -Aminobutyric Acid (GABA) System
    • Benzodiazepine receptor
      • gates the Cl– channel
      • Part of the GABA A receptor complex
    • In epilepsy
      • Flumazenil
        • Reduced benzodiazepine receptor density
        • more sensitive and more accurate for focus localization than 18 F-FDG
  • 40. γ -Aminobutyric Acid (GABA) System
    • Degenerative disorders
      • Huntington's disease
        • A loss of GABA A receptor–carrying neurons
          • in the caudate and putamen
      • In some cerebellar ataxias
        • Benzodiazepine receptor density in the cerebellum is reduced early
    • In early Alzheimer's disease
      • Glucose hypometabolism
      • Preserved benzodiazepine-binding sites -> intact cortical neurons
  • 41. γ -Aminobutyric Acid (GABA) System
    • In ischemic stroke
      • Flumazenil
        • detect irreversible tissue damage
        • invasive therapeutic strategies ?
    • In schizophrenia
      • psychotic symptoms
        • reduced benzodiazepine receptor binding in limbic cortical regions
  • 42. γ -Aminobutyric Acid (GABA) System
    • Panic and anxiety disorders
      • Reduced receptor binding in the temporal, occipital, and frontal lobes.
  • 43. ADENOSINE RECEPTORS
  • 44. Adenosine Receptors
    • A 1 and A 2A
      • Neuromodulation
      • A 1 receptor
        • The labeled xanthine analogs 18 F-CPFPX and 11 C-MPDX are ligands.
        • High density in the putamen and mediodorsal thalamus.
    • Prediction of severe tissue damage in early states of ischemic stroke .
  • 45. OPIOID RECEPTORS
  • 46. Opioid Receptors
    • Perception and emotional processing of pain
    • 11 C-carfentanyl
      • ligand for the µ receptors,
      • pleasurable reward feeling,
      • highest concentrations in the basal ganglia and thalamus
    • 18 F-Cyclofoxy
      • antagonist to µ and k subtypes,
  • 47. CONCLUSION
  • 48. Conclusion
    • Receptors have a central role in neurotransmission and neuromodulation and are involved in all brain functions.
  • 49. Conclusion
    • The imaging of the distribution, density, and activity of various receptors therefore permits insight into the physiologic activities of functional networks and their disturbance by neurologic and psychiatric disorders and can be used for studying selective drug action .
  • 50. Have a nice day !