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Traditional receptor theory and its application to neuroreceptor measurements in functional imaging

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Abstract

The mathematical, biological discipline of receptor pharmacology and the graphical methods of describing receptor behaviour evolved over a century of painstaking observation and model testing. Laws regarding in vitro theories are classically considered inoperative in vivo. Nevertheless, functional imaging techniques have rapidly evolved to allow receptor measurement and rules of thumb have been developed which clearly prove valid receptor parameters can be derived from functional imaging studies. The field is evolving so rapidly now that nuclear medicine researchers are in danger in applying these techniques without recourse to an understanding of the orthodox discipline of receptor pharmacology. This review attempts to document the basis of receptor pharmacology and to give an account of the theoretical and practical basis on which this can be applied in vivo. The review is targeted towards single-photon emission tomography because of the rapid growth in the area, but many parts draw on the literature relating to positron emission tomography since the first translation of in vitro to in vivo measurement was performed with this technique.

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References

  1. Dean PM.Molecular foundations of drug receptor interactions. Cambridge: Cambridge University Press, 1988.

    Google Scholar 

  2. Taylor P, Insel PA. Molecular basis of pharmacological selectivity. In: Pratt WB, Taylor P, eds.Principles of drug action: the basis of pharmacology. London: Churchill Livingstone; 1990:1–103.

    Google Scholar 

  3. Clark AJ.The mode of action of drugs on cells. London: Edward Arnold, 1933.

    Google Scholar 

  4. Scatchard G. The attractions of proteins for small molecules and ions.Ann NY Acad Sci 1949; 51:660–665.

    Google Scholar 

  5. Hill AV. The combination of haemoglobin with oxygen and with carbon monoxide.Biochemical J 1913; 7:471–480.

    Google Scholar 

  6. Seibyl JP. Development of SPET as a tool for neuropsychopharmacological research. In: Kerwin R, ed.Neurobiology and psychiatry, vol III. Cambridge: Cambridge University Press, 1995.

    Google Scholar 

  7. Innis R, Al-Tikriti M, Zoghbi S, etal. SPECT imaging of the benzodiazepine receptor, feasibility of in vivo potency measurement from stepwise displacement curves.J Nucl Med 1991; 32:1754–1761.

    PubMed  Google Scholar 

  8. Pedigo NW, Yamamura HI, Nelson DL. Discrimination of multiple3H-5-hydroxy tryptamine binding sites by the neuroleptic spiperone in rat brain.J Neurochem 1981; 36:220–226.

    PubMed  Google Scholar 

  9. Oldendorf WH. Lipid solubility and drug penetration of the blood brain barrier.Proc Soc Exp Biol Med 1974; 147:813–816.

    PubMed  Google Scholar 

  10. Rall D, Stabonau JR, Zubrod CG. Distribution of drugs between blood and cerebrospinal fluid. General methodology and effect of pH gradients.J Pharmacol Exp Ther 1959; 125:185–190.

    PubMed  Google Scholar 

  11. Helmer F, Kiens K, Hansch C. The linear free energy relationship between partition co-efficients and the binding and conformational perturbation of macromolecules by small organic compounds.Biochemistry 1968; 7:2858–2863.

    PubMed  Google Scholar 

  12. Young AB, Frey KA, Agranoff BW. Receptor assays: in vitro and in vivo. In: Phelps M, Mazziotta J, Schelbert H, eds.Positron emission tomography and autoradiography: principles and applications for the brain and heart. New York: Raven Press; 1986.

    Google Scholar 

  13. Dolan R, Bench C, Friston K. Positron emission tomography in psychopharmacology.Int Rev Psychiatry 1990; 2:427–439.

    Google Scholar 

  14. Costa DC, Verhoeff NPLG, Cullum ID, Ell PJ etal. In vivo characterization of 3-iodo-6-methoxy benzamide 123-I in humans.Eur J Nucl Med 1990; 16:813–816.

    PubMed  Google Scholar 

  15. Brucke T, Roth J, Piedreka I, Strobi R, Wenger S, Asendaum S. Striatal D2 receptor blockade by typical and atypical neuroleptics.Lancet 1992; 339:497.

    PubMed  Google Scholar 

  16. Pilowsky LS, Costa DC, Ell PJ, Murray RM, Kerwin RW. Clozapine, single photon emission tomography and D2 dopamine receptor blockade hypothesis of schizophrenia.Lancet 1992; 340:199–202.

    PubMed  Google Scholar 

  17. Laruelle M, Wallace E, Seibyl JP etal. Graphical, kinetic and equilibrium analysis of in vivo (123 I)β-CIT binding to dopamine transporters in healthy human subjects.J Cereb Blood Flow Metab 1994; 14:982–994.

    PubMed  Google Scholar 

  18. Logan J, Wolf AP, Shine CY, Fowler JS. Kinetic modelling of receptor ligand binding applied to positron emission tomography: studies with neuroleptic tracers.J Neurochem 1987; 48:73–83.

    PubMed  Google Scholar 

  19. Frost JJ, Douglas KH, Mayberg HS, etal. Multicompartmental analysis of11C-carfentanil binding to opiate receptors in humans measured by positron emission tomography.J Cereb Blood Flow Metab 1989; 9:398–409.

    PubMed  Google Scholar 

  20. Farde L, Wiesel FA, Stone-Elander S, Halldin C, Nordstrom AL, Hall H, Sedvall G. D2 dopamine receptors in neuroleptic naive schizophrenic patients.Arch Gen Psychiatry 1990; 47:213–219.

    PubMed  Google Scholar 

  21. Bjorklund A, Hokfelt T, eds. Handbook of chemical neuroanatomy, vol 4. GABA and neuropeptides in the CNS, part 1. Amsterdam: Elsevier, 1985.

    Google Scholar 

  22. Johnstone EC, Crow TJ, Frith CD, Carney MWP, Price JS. Mechanism of the antipsychotic effect in the treatment of acute schizophrenia.Lancet 1978; 1:848–851.

    PubMed  Google Scholar 

  23. Crow TJ. Molecular pathology of schizophrenia: more than one disease process.Br Med J 1980; 280:66–68.

    PubMed  Google Scholar 

  24. Mackay AVP, Iversen LL, Rossor M, etal. Increased brain dopamine and dopamine receptors in schizophrenics.Arch Gen Psychiatry 1982; 39:991–997.

    PubMed  Google Scholar 

  25. Crawley JCW, Crow TJ, Johnstone EC, etal. Uptake of Brspiperone in the striata of schizophrenic patients and controls.Nucl Med Commun 1986; 7:599–607.

    PubMed  Google Scholar 

  26. Wong DF, Wagner HN, Tune LE, etal. Positron emission tomography reveals elevated D2 receptors in drug naive schizophrenics.Science 1986; 234:1558–1563.

    PubMed  Google Scholar 

  27. Wong DF, Pearlson GD, Young CT, etal. Dopamine receptors are elevated in neuropsychiatric disorders other than schizophrenia.J Cereb Blood Flow Metab 1989; 9 Suppl 1:S593.

    Google Scholar 

  28. Tune LE, Wong DF, Pearlson G. Elevated dopamine 2 receptor density in 23 schizophrenic patients: a positron emission tomography study with11C-n-methylspiperone.Schizophr Res 1992; 22:17.

    Google Scholar 

  29. Martinot JL, Peron-Magnan P, Huret JD etal. Striatal D2 dopaminergic receptors assessed with positron emission tomography and 76 Br-bromospiperone in untreated schizophrenic patients.Am J Psychiatry 1990; 147:44–50.

    PubMed  Google Scholar 

  30. Martinot JL, Pailliere-Martinot ML, Loc'h C, etal. The estimated density of D2 striatal receptors in schizophrenia. A study with positron emission tomography and76bromolisu-ride.Br J Psychiatry 1991; 158:346–350.

    PubMed  Google Scholar 

  31. Pilowsky LS, Costa DC, Ell PJ, etal. D2 dopamine receptor binding in the basal ganglia of antipsychotic free schizophrenic patients: a 123-I IBZM single photon emission tomography (SPET) study.Br J Psychiatry 1994, 164:16–26.

    PubMed  Google Scholar 

  32. Kessler RM, Votaw J, Schmidt D, etal. High affinity dopamine D2 receptor ligands 3. 123-I epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain.Life Sci 1993; 53:241–250.

    PubMed  Google Scholar 

  33. Savic I, Persson A, Roland P, etal. In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci.Lancet 1988; II:863–866.

    Google Scholar 

  34. Savic I, Thorell JO. PET shows different pattern of benzodiazepine receptor changes in intractable compared with moderate partial epilepsy.J Cereb Blood Flow Metab 1993, 13 Suppl:S278.

    Google Scholar 

  35. Prevett MC, Lammertsma AA, Duncan JS, etal. Central benzodiazepine receptor quantification (BZR) in normal subjects and primary generalized epilepsy.J Cereb Blood Flow Metab 1993; 13 Suppl 1:S277.

    Google Scholar 

  36. Wyper DJ, Brown D, Patterson J, etal. Density of acetylcholine receptors in Alzheimer's disease measured in relation to regional cerebral blood flow.J Cereb Blood Flow Metab 1993; 13 Suppl 1.

  37. Blin J, Baron JC, Dubouis B, etal. Loss of brain 5HT2 receptors in Alzheimer's disease.Brain 1993; 116:497–510.

    PubMed  Google Scholar 

  38. Volkow ND, Fowler JS, Wolf AP, etal. Effects of chronic cocaine abuse on postsynaptic dopamine receptors.Am J Psychiatry 1990; 147:719–724.

    PubMed  Google Scholar 

  39. Volkow ND, Fowler JS, Wang GJ. Decreased dopamine D, receptor availability is associated with reduced frontal metabolism in cocaine abusers.Synapse 1993; 14:169–177.

    PubMed  Google Scholar 

  40. Litton JF, Nieman J, Pauli S, etal. PET analysis of 11C-flumazenil binding to benzodiazepine receptors in chronic alcohol dependent men and healthy controls.Psychiatry Res Neuroinzaging 1993; 50:1–13.

    Google Scholar 

  41. Heninger GR, Charney DS. Mechanism of action of antidepressant treatments. Implications for the etiology and treatment of depressive disorders. In: Meltzer HY, ed. Psychopharmacology: the third generation of progress. New York: Raven Press; 1987.

    Google Scholar 

  42. Hallstrom C. Benzodiazepines: clinical practice and central mechanisms. In: Granville-Grossman K, ed. Recent advances in clinical psychiatry, no 5. London: Churchill Livingstone, 1985.

    Google Scholar 

  43. Feistel H, Kaschka WP, Ebert D, et al. Assessment of cerebral benzodiazepine receptor distribution in anxiety disorders: a study with 123-I-lomazenil.J Nucl Med 1993; 34 Suppl 15:47.

    Google Scholar 

  44. Murphy DL, Zohar J, Benkerfat C, etal. Obsessive compulsive disorder as a 5-HT subsystem related behavioural disorder.Br J Psychiatry 1989; 155 Suppl 8:15–24.

    Google Scholar 

  45. Peroutka SJ, Snyder SH. Relationship of neuroleptic drug effects at brain dopamine, serotonin, alpha adrenergic and histamine receptors to clinical potency.Am J Psychiatry 1980; 137:1518–1522.

    PubMed  Google Scholar 

  46. Smith M, Wolf AP, Brodie JD, etal. Serial18F-n-methylspiroperidol PET studies to measure changes in antipsychotic drug D2 receptor occupancy in schizophrenic patients.Biol Psychiatry 1988; 23:653–663.

    PubMed  Google Scholar 

  47. Cambon H, Baron JC, Boulenger JP, etal. In vivo assay for neuroleptic receptor binding in the striatum.Br J Psychiatry 1987; 151:824–830.

    PubMed  Google Scholar 

  48. Lundberg T, Lindstrom LH, Hartnig P, etal. Striatal and frontal cortex binding of11C labelled clozapine visualized by positron emission tomography in drug free schizophrenics and healthy volunteers.Psychopharmacology 1989; 99:8–12.

    PubMed  Google Scholar 

  49. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G. Positron emission tomographic analysis of central D1 and D2 receptor occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects.Arch Gen Psychiatry 1992; 49:538–544.

    PubMed  Google Scholar 

  50. Nordstrom AL, Farde L, Halldin C. High 5HT2 receptor occupancy in clozapine treated patients demonstrated by PET.Psychopharmacology 1993; 110:365–367.

    PubMed  Google Scholar 

  51. Busatto GF, Pilowsky LS, Costa DC, etal. Dopamine D2 receptor blockade in vivo with the novel antipsychotics risperidone and remoxipride: a 123-I IBZM single photon emission tomography (SPET) study.Psychopharmacology 1995; 117:55–61.

    PubMed  Google Scholar 

  52. Wolkin A, Barouche F, Wolf AP, etal. Dopamine blockade and clinical response: evidence for two biological subgroups of schizophrenics.Am J Psychiatry 1989; 146:905–908.

    PubMed  Google Scholar 

  53. Pilowsky LS, Costa DC, Ell PJ, etal. Antipsychotic medication, D2 dopamine receptor blockade and clinical response: a 123-I IBZM SPET (single photon emission tomography) study.Psychol Med 1993; 23:791–797.

    PubMed  Google Scholar 

  54. Nyberg S, Farde L, Eriksson L, etal. 5HT2 and D2 dopamine receptor occupancy in the living human brain.Psychopharmacology 1993; 110:265–272.

    PubMed  Google Scholar 

  55. Seibyl J, Syrbirska E, Brenner D, etal. I-123-lomazenil SPECT brain imaging demonstrates significant receptor reserve in human and non human primate brain.J Nucl Med 1993; 34:102.

    Google Scholar 

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  1. Institute of Psychiatry, De Crespigny Park, SE5 8AF, London, UK

    Robert W. Kerwin & Lyn S. Pilowsky

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  1. Robert W. Kerwin
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  2. Lyn S. Pilowsky
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Kerwin, R.W., Pilowsky, L.S. Traditional receptor theory and its application to neuroreceptor measurements in functional imaging. Eur J Nucl Med 22, 699–710 (1995). https://doi.org/10.1007/BF01254574

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