This review discusses the current use of single photon emission computerised tomography (SPECT) for central benzodiazepine receptor imaging and quantitation. The general principles underlying SPECT imaging and receptor quantitation methods such as the kinetic, pseudo-equilibrium and steady-state (tracer infusion and bolus) approaches are described. The advantages and practical drawbacks of these techniques are highlighted.
Abadie P., Baron J.C., Bisserbe J.C., Boulenger J.P., Rioux P., Travere J.M., Barre L., Petit-Taboue M.C., Zarifian E. (1992) Central benzodiazepine receptors in human brain: estimation of regional Bmax and Kd values with positron emission tomography. Eur J Pharmacol213:107-115
2.
Abi-Dargham A., Laruelle M., Seibyl J., Rattner Z., Baldwin R.M., Zoghbi S.S., Zea-Ponce Y., Bremner J.D., Hyde T.M., Charney D.S., Hoffer P.B., Innis R.B. (1994) SPECT measurement of benzodiazepine receptors in human brain with [123I]iomazenil: kinetic and equilibrium paradigms. J Nucl Med35: 228-238
3.
Bailey D.L., Zito F., Gilardi M., Savi A.R., Fazio F., Jones T. (1994) Performance comparison of a state-of-the-art neuro-SPET scanner and a dedicated neuro-PET scanner. Eur J Nucl Med21: 381-387
4.
Beer H.F., Blauenstein P.A., Hasler P.H., Delaloye B., Riccabona G., Bangerl I., Hunkeler W., Bonetti E.P., Pieri L., Richards J.G., Schubiger P.A. (1990) In vitro and in vivo evaluation of iodine-123 Ro 16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors . J Nucl Med31:1007-1014
5.
Blokland J A K (1994) Expectation maximization in quantitative single-photon emission tomography. Eur J Nucl Med21: 595-596
6.
Blokland J A K, Reiber J H C, Pauwels E K J (1992) Quantitative analysis in single photon emission tomography (SPET). Eur J Nucl Med19: 47-61
7.
Braestrup C., Squires R.F. (1977) Specific benzodiazepine receptors in rat brain characterized by high affinity [3H]diazepam binding. Proc Natl Acad Sci USA74: 3805-3809
8.
Braestrup C., Albrechtsen R., Squires R.F. (1977) High densities of benzodiazepine receptors in human cortical areas. Nature269: 702-704
9.
Buck A., Westera G., Burger C., Schulthess G.K. (1994a) Modelling of [123I]iomazenil brain kinetics. Eur J Nucl Med21: S108, 423
10.
Buck A., Westera G., Burger C., Schulthess G.K. (1994b) Modelling of [123I]iomazenil with calculated metabolite correction. Eur J Nucl Med21: S14,48
11.
Carson R.E. (1991a) Precision and accuracy considerations of physiological quantification in PET. J Cerebral Blood Flow Metab11: A45-A50
12.
Carson R.E. (1991b) The development and application of mathematical models in nuclear medicine. J Nucl Med32: 2206-2208
13.
Carson R.E., Channing M.A., Blasberg R.G., Dunn B.B., Cohen R.M., Rice K.C., Herscovitch P. (1993) Comparison of bolus and infusion methods for receptor quantitation: application to [18F]cyclofoxy and positron emission tomography . J Cerebral Blood Flow Metab13: 24-42
14.
Dannals R.F., Ravert H.T., Wilson A.A. (1990) Radiochemistry of tracers for neurotransmitter receptor studies. In Frost J J, Wagner H M (eds), Quantitative imaging; neuroreceptors, neurotransmitters and enzymes. Raven Press, New York, pp.19-35
15.
Dauth J., Holl K., Deisenhammer E. (1990) Time curves of radioactivity in plasma after injection of Iomazenil Ro 16-0154. In Schubiger P A , Hasler P H (eds), Iomazenil and other brain receptor tracers for SPECT Editones Roche, Basel, Switzerland, pp. 33-41
16.
Delforge J., Syrota A., Bottlaender M., Varastet M., Loc'h C., Bendriem B., Crouzel C., Brouillet E., Maziere M. (1993) Modeling analysis of [11C]flumazenil kinetics studied by PET: application to a critical study of the equilibrium approaches. J Cerebral Blood Flow Metab13: 454-468
17.
Delforge J., Pappata S., Millet P., Samson Y., Bendriem B., Jobert A., Crouzel C., Syrota A. (1995) Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cerebral Blood Flow Metab15: 284-300
18.
Dey H.M., Seibyl J.P., Stubbs J.B., Zoghbi S.S., Baldwin R.M., Smith E.O., Zubal I.G., Zea-Ponce Y., Olson C., Charney D.S., Hoffer P.B., Innis R.B. (1994) Human biodistribution and dosimetry of the SPECT benzodiazepine receptor radioligand Iodine-123-iomazenil. J Nucl Med35: 399-404
19.
Frey K.A., Ehrenkaufer L.E., Beaucage S., Agranoff B.W. (1985) Quantitative in vivo receptor binding I. Theory and application to the muscarinic cholinergic receptor. J Neurosci5: 421-428
20.
Frost J.J., Wagner H.N. (1990) Quantitative imaging: neuroreceptors, neurotransmitters and enzymes. Raven Press, New York
21.
George M.S., Ring H.A., Costa D.C., Ell P.J., Kouris K., Jarritt P.H. (1991) Neuroactivation and neuroimaging with SPET. Springer-Verlag, Berlin
22.
Gjedde A., Wong D.F. (1990) Modelling neuroreceptor binding of radioligands in vivo. In Frost J J, Wagner H N (eds), Quantitative imaging; neuroreceptors, neurotransmitters and enzymes. Raven Press, New York, pp. 51-80
23.
Holthoff V.A., Koeppe R.A., Frey K.A., Paradise A.H., Kuhl D.E. (1991) Differentiation of radioligand delivery and binding in the brain: validation of a two-compartment model for [11C]flumazenil. J Cerebral Blood Flow Metab11: 745-752
24.
Holl K., Deisenhammer E., Dauth J., Carmann H., Schubiger P.A. (1989) Imaging benzodiazepine receptors in the human brain by single photon emission computed tomography (SPECT). Nucl Med Biol16:759-763
Innis R.B., Al-Tikriti M.H., Zoghbi S.S., Baldwin R.M., Sybirska E.H., Laurelle M.A., Malison R.T., Seibyl J.P., Zimmermann R.C., Johnson E.W., Smith E.O., Charney D.S., Heninger G.R., Woods S.W., Hoffer P.B. (1991a) SPECT imaging of the benzodiazepine receptor: feasibility of in vivo potency measurements from stepwise displacement curves . J Nucl Med32: 1754-1761
27.
Innis R.B., Zoghbi S.S., Johnson E.W., Woods S.W., Al-Tikriti M.H., Baldwin R.M., Seibyl J.P., Malison R.T., Zubal G., Charney D.S., Heninger G.R., Hoffer P.B. (1991b) SPECT imaging of the benzodiazepine receptor in non-human primate brain with [123I]Ro 16-0154. EurJ Pharmacol193:249-252
28.
Iyo M., Itoh T., Yamasaki T., Fukuda H., Inoue O., Shinotoh H., Suzuki K., Fukui S., Tateno Y. (1991) Quantitative in vivo analysis of benzodiazepine binding sites in the human brain using positron emission tomography. Neuropharmacology30: 207-215
29.
Izquierdo I, Medina (1993) Naturally occurring benzo-diazepinesstructure, distribution and function. Ellis Horwood, London
30.
Johnson E.W., Woods S.W., Zoghbi S., McBride B.J., Baldwin R.M., Innis R.B. (1990) Receptor binding characterization of the benzodiazepine radioligand 125I-Ro 16-0154: a potential probe for SPECT brain imaging. Life Sci47:1535-1546
31.
Kawai R., Carson R.E., Dunn B., Newman A.H., Rice K.C., Blasberg R.G. (1991) Regional brain measurement of Bmax and KD with the opiate antagonist cyclofoxy: equilibrium studies in the conscious rat. J Cerebral Blood Flow Metab11: 529-544
32.
Kety S.S., Schmidt C.F. (1948) The nitrous oxide method for the quantitative determination of cerebral blood flow in man: theory, procedure and normal values. J Clin Lab Invest27: 476-483
33.
Koeppe R.A., Holthoff VA, Frey K.A., Kilbourn M.R., Kuhl D.E. (1991) Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cerebral Blood Flow Metab11: 735-744
34.
Kung H.F. (1993) SPECT and PET ligands for CNS Imaging. Neurotransmissions9: 1-7
35.
Laurelle M., Abi-Dargham A., Rattner Z., Al-Tikriti M.S., Zea-Ponce Y., Zoghbi S.S., Charney D.S., Price J., Frost J., Hoffer P., Baldwin R.M., Innis R.B. (1993) Single photon emission tomography measurement of benzodiazepine receptor number and affinity in primate brain: a constant infusion paradigm with [123I]iomazenil. Eur J Pharmacol230:119-123
36.
Laruelle M., Baldwin R.M., Rattner Z., Al-Tikriti M.S., Zea-Ponce Y., Zoghbi S.S., Charney D.S., Price J.C., Frost J.J., Hoffer P.B., Innis R.B. (1994a) SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in non-human primates: kinetic analysis of single bolus experiments. J Cerebral Blood Flow Metab14:439-452
37.
Laruelle M., Abi-Dargham A., Al-Tikriti M.S., Baldwin R.M., Zea-Ponce Y., Zoghbi S.S., Charney D.S., Hoffer P., Innis R.B. (1994b) SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in non-human primates: equilibrium analysis of constant infusion experiments and correlation with in vitro parameters. J Cerebral Blood Flow Metab14: 453-465
38.
Lassen N.A. (1992) Neuroreceptor quantitation in vivo by the steady-state principle using constant infusion or bolus injection of radioactive tracers . J Cerebral Blood Flow Metab12: 709-716
39.
Lassen N.A., Gjedde A. (1983) Tracer kinetics and physiologic modeling. In Lambrecht R M, Rescigno A (eds), Lecture notes in biomathematics, vol. 48. Springer Verlag, New York, pp. 387-410
40.
Lassen N.A., Perl W. ( 1979) Tracer kinetic methods in medical physiology. Raven Press, New York
41.
Lassen N.A., Bartenstein P.A., Lammertsma A.A., Prevett M.C., Turton D.R., Luthra S.K., Osman S., Bloomfield P.M., Jones T., Patsalos P.N., O'Connell M.T., Duncan J.S., Andersen J.V. (1995) Benzodiazepine receptor quantification in vivo in human using C-11-flumazenil and PET: application of the steady-state principle . J Cerebral Blood Flow Metab15: 152-165
42.
Litton J.E., Neiman J., Paulis S., Farde L., Hindmarsh T., Halldin C., Sedvall G. (1993) PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol-dependent men and healthy controls. Psychiatr Res: Neuroimaging50: 1-13
43.
Litton J.E., Hall H., Pauli S. (1994) Saturation analysis in PET— analysis of errors due to imperfect reference regions. J Cerebral Blood Flow Metab14: 358-361
44.
McBride B.J., Baldwin R.M., Kerr J.M., Wu J.L. (1991) A simple method for the preparation of [123I] and [125I] labelled iodobenzodiazepines. Appl Radiat Isotopes42:173-175
45.
Miller L.G. (1991) Chronic benzodiazepine administration: from the patient to the gene. J Clin Pharmacol31: 492-495
46.
Mintun M.A., Raichle M.E., Kilbourn M.R., Wooten G.F., Welch M.J. (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol15: 215-227
47.
Moerlein S.M., Welch M.J. (1991) Application of SPECT to the in vivo measurement of benzodiazepine potency. J Nucl Med32: 1762-1763
48.
Mohler H., Okada T. (1977) The benzodiazepine receptor: demonstration in the central nervous system. Science198: 849-851
49.
Nordberg A. (1992) Neuroreceptor changes in Alzheimer's disease. Cerebrovascular Brain Metab Rev4: 303-328
50.
Nutt D., Lawson C. (1992) Panic attacks - a neurochemical overview of models and mechanisms. Br J Psychiatr160:165-178
51.
Pappata S., Samson Y., Chavoix C., Prenant C., Maziere M., Baron J.C. (1988) Regional specific binding of [11C]RO 151788 to central type benzodiazepine receptors in human brain: quantitative evaluation by PET. J Cerebral Blood Flow Metab8: 304-313
52.
Pauli S., Liljequist S., Farde L., Swahn C.G., Halldin C., Litton J.E., Sedvall G. (1992) Analysis of alcohol interaction with the brain disposition of [11C]flumazenil. Psychopharmacology107: 180-185
53.
Perl W. ( 1971) Stimulus-response method for flows and volumes in slightly perturbed constant parameter systems. Bull Math Biophys33: 225-233
54.
Pike V.W. (1993) Positron-emitting radioligands for studies in vivo — probes for human psychopharmacology. J Psychopharmacol7: 139-158
55.
Pilowsky L.S., Costa D.C., Ell P.J., Verhoeff L.G., Murray R.M., Kerwin R.W. (1994) D2 Dopamine receptor binding in the basal ganglia of antipsychotic-free schizophrenic patients: an 123I-IBZM single photon emission computerised tomography study. Br J Psychiatr164: 16-26
56.
Price J.C., Mayberg H.S., Dannals R.F., Wilson A.A., Ravert H.T., Sadzot B., Rattner Z., Kimball A., Feldman M.A., Frost J.J. (1993) Measurement of benzodiazepine receptor number and affinity in humans using tracer kinetic modelling, positron emission tomography, and [11C]flumazenil. J Cerebral Blood Flow Metab13: 656-667
57.
Reba R.C. (1993) PET and SPECT: opportunities and challenges for psychiatry. J Clin Psychiatr54 (Suppl 11): 26-32
58.
Richards J.G., Mohler H. (1984) Benzodiazepine receptors. Neuropharmacology23: 233-242
Rothstein J.D. (1994) Benzodiazepine-receptor ligands and hepatic encephalopathy: a causal relationship? Hepatology19: 248-250
61.
Saji H., Iida Y., Nakatsuka I., Kataoka M., Ariyoshi K., Magata Y., Yoshitake A., Yokoyama A. (1993) Radioiodinated 2'iododiazepam : a potential imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med34: 932-937
62.
Samson Y., Hantraye P., Baron J.C., Soussaline F., Comar D., Maziere M. (1985) Kinetics and displacement of [11C]Ro 15 1788, a benzodiazepine antagonist, studied in human brain in vivo by positron tomography . Eur J Pharmacol110: 247-251
63.
Savic I., Persson A., Roland P., Pauli S., Sedvall G., Widen L. (1988) In vivo demonstration of reduced benzodiazepine receptor binding in human epileptic foci. Lancetii: 863-866
64.
Scatchard G. (1949) The attractions of proteins for small molecules and ions. Ann N Y Acad Sci51: 660-672
65.
Schlegel S., Steinert H., Bockisch A., Hahn K., Schloesser R., Benkert O. (1994) Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil-SPECT. Eur Arch Psychiatr Clin Neurosci244: 49-51
66.
Sedvall G., Farde L., Persson A., Wiesel F.A. (1986) Imaging of neurotransmitter receptors in the living human brain. Arch Gen Psychiatr43: 995-1005
67.
Shimohama S., Tanigushi T., Fujiwara M., Kameyama M. (1988) Changes in benzodiazepine receptors in Alzheimer-type dementia. Ann Neurol23:404-406
68.
Shinotoh H., Yamasaki T., Inoue O., Itoh T., Suzuki K., Hashimoto K., Tateno Y., Ikehira H. (1986) Visualization of specific binding sites of benzodiazepine in human brain. J Nucl Med27: 1593-1599
69.
Sieghart W. (1989) Multiplicity of GABA-A benzodiazepine receptors . Trends Pharmacol Sci10: 407-411
70.
Sieghart W. (1992) GABAA receptors: ligand-gated Cl- ion channels modulated by multiple drug-binding sites. Trends Pharmacol Sci13:446-450
71.
Sieghart W., Item C., Buchstaller A., Fuchs K., Higer H., Adamiker D. (1993) Evidence for the existence of differential O-glycosylated α5-subunits of the γ-aminobutyric acid-A receptor in the rat brain. J Neurochem60: 93-98
72.
Stoddart H.F., Stoddart H.A. (1979) A new development in single gamma transaxial tomography. Union Carbide Focussed Collimator scanner. IEEE Trans Nucl Sci26: 2710-2712
73.
Sybirska E., Seibyl J.P., Bremner J.D., Baldwin R.M., Al-Tikriti M.S., Bradberry C., Malison R.T., Zea-Ponce Y., Zoghbi S., During M., Goddard A.W., Woods S.W., Hoffer P.B., Charney D.S., Innis R.B. (1993) [123I]Iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain. Neuropharmacology32: 671-680
74.
Twyman R.E., Rogers C.J., Macdonald R.L. (1989) Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbitol. Ann Neurol25: 213-220
75.
Verhoeff N. P L G, Erbas B., Kapucu O., Sokole E.B., Blok H., Van-Royen E.A. (1993) Quantification of central benzodiazepine receptor binding potential in the brain with 123I-iomazenil SPECT: technical and interobserver variabilityNucl Med Commun14: 634-643
76.
Videbaek C., Friberg L., Holm S., Wammen S., Foged C., Andersen J.V., Dalgaard L., Lassen N.A. (1993) Benzodiazepine receptor equilibrium constants for flumazenil and midazolam determined in humans with single photon emission computer tomography tracer [123I]iomazenil. Eur J Pharmacol249: 43-51
77.
Westera G., Buck A., Burger C., Leenders K., Schubiger G.K., Schulthess V. (1994) [11C]Iomazenil PET versus [123I]iomazenil SPECT . Eur J Nucl Med21: S14, 47
78.
Whitehouse P.J., Trifiletti R.R., Jones B.E., Folstein S., Price D.L., Snyder S.H., Kuhar M.J. (1985) Neurotransmitter receptor alteration in Huntington's disease: autoradiographic and homogenate studies with special reference to benzodiazepine receptor complexes. Ann Neurol18: 202-210
79.
Woods S.W., Seibyl J.P., Goddard A.W., Dey H.M., Zoghibi S.S., Germine M., Baldwin R.M., Smith E.O., Charney D.S., Heninger G.R., Hoffer P.B., Innis R.B. (1992) Dynamic SPECT imaging of the benzodiazepine receptor in healthy human subjects with [123I]Ro 16-0154. Psychiatr Res: Neuroimaging47: 67-77
