Position Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) can be used for both pharmacokinetic and pharmacodynamic measures in vivo in man. As such they have a wide range of applications including description of neurochemical changes in disease, occupancy, brain effects of medicines and discovery and validation of biomarkers. The power of these tools is in their chemical specificity and sensitivity, and in the ability to describe processes in vivo, thus documenting the effects of genetic and environmental interactions. The future of these technologies is dependent on an investment in bringing out and validating new radiotracers.
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References
1.
Abi-Dargham A, Innis R B, Wisniewski G, Baldwin R M, Neumeyer J L, Seibyl J P (1997) Human biodistribution and dosimetry of iodine-123-fluoroalkyl analogs of beta-CIT. European Journal of Nuclear Medicine24: 1422–1425.
2.
Abi-Dargham A, Kegeles L S, Martinez D, Innis R B, Laruelle M (2003) Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naive healthy volunteers: results from a large cohort. European Neuropsychopharmacology13: 459–468.
3.
Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang D R, Keilp J, Kochan L, Van Heertum R, Gorman J M, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. Journal of Neuroscience22: 3708–3719.
4.
Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends in Neurosciences19: 378–383.
5.
Aston J A, Cunningham V J, Asselin M C, Hammers A, Evans A C, Gunn R N (2002) Positron emission tomography partial volume correction: estimation and algorithms. Journal of Cerebral Blood Flow & Metabolism22: 1019–1034.
6.
Blier P, Bergeron R, (1995) Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. Journal of Clinical Psychopharmacology15: 217–222.
7.
Cumming P, Yokoi F, Chen A, Deep P, Dagher A, Reutens D, Kapczinski F, Wong D F, Gjedde A (1999) Pharmacokinetics of radiotracers in human plasma during positron emission tomography. Synapse34: 124–134.
8.
Farde L, Nordstrom A L, Nyberg S, Halldin C, Sedvall G (1994) D1-, D2-, and 5-HT2-receptor occupancy in clozapine-treated patients. Journal of Clinical Psychiatry55Suppl B: 67–69.
9.
Farde L, Nordstrom A L, Wiesel F A, Pauli S, Halldin C, Sedvall G (1992) Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Archives of General Psychiatry49: 538–544.
10.
Farde L, Wiesel F A, Nordstrom A L, Sedvall G, (1989) D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology99Suppl S: 28–31.
11.
Gefvaert O, Lundberg T, Wieselgren I M, Bergstrom M, Langstrom B, Wiesel F, Lindstrom L (2001) D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study. European Neuropsychopharmacology11: 105–110.
12.
Gunn R N, Gunn S R, Cunningham V J (2001) Positron emission tomography compartmental models. Journal of Cerebral Blood Flow & Metabolism21: 635–652.
13.
Gunn R N, Gunn S R, Turkheimer F E, Aston J A, Cunningham V J (2002) Positron emission tomography compartmental models: a basis pursuit strategy for kinetic modeling. Journal of Cerebral Blood Flow & Metabolism22: 1425–1439.
14.
Gunn R N, Lammertsma A A, Hume S P, Cunningham V J (1997) Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage6: 279–287.
15.
Ito H, Hietala J, Blomqvist G, Halldin C, Farde L (1998) Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [11C]raclopride binding. Journal of Cerebral Blood Flow & Metabolism18: 941–950.
16.
Kapur S, Zipursky R, Jones C, Shammi C S, Remington G, Seeman P (2000) A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Archives of General Psychiatry57: 553–559.
17.
Laakso A, Pohjalainen T, Bergman J, Kajander J, Haaparanta M, Solin O, Syvalahti E, Hietala J (2005) The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L-amino acid decarboxylase in healthy subjects. Pharmacogenetics & Genomics15: 387–391.
18.
Lammertsma A A., Hume S P (1996) Simplified reference tissue model for PET receptor studies. Neuroimage4: 153–158.
19.
Laruelle M, Slifstein M, Huang Y (2002) Positron emission tomography: imaging and quantification of neurotransporter availability. Methods27: 287–299.
20.
Laruelle M, Slifstein M, Huang Y (2003) Relationships between radio-tracer properties and image quality in molecular imaging of the brain with positron emission tomography. Molecular Imaging & Biology5: 363–375.
21.
Lingford-Hughes A R, Acton P D, Gacinovic S, Suckling J, Busatto G F, Boddington S J, Bullmore E, Woodruff P W, Costa D C, Pilowsky L S, Ell P J, Marshall E J, Kerwin R W (1998) Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy. British Journal of Psychiatry173: 116–122.
22.
Lingford-Hughes A R, Wilson S J, Cunningham V J, Feeney A, Stevenson B, Brooks D J, Nutt D J (2005) GABA-benzodiazepine receptor function in alcohol dependence: a combined 11C-flumazenil PET and pharmacodynamic study. Psychopharmacology180: 595–606.
23.
Lubberink M, Boellaard R, van der Weerdt A P, Visser F C, Lammertsma A A (2004) Quantitative comparison of analytic and iterative reconstruction methods in 2- and 3-dimensional dynamic cardiac 18F-FDG PET. Journal of Nuclear Medicine45: 2008–2015.
24.
Malizia A L, Cunningham V J, Bell C J, Liddle P F, Jones T, Nutt D J (1998) Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Archives of General Psychiatry55: 715–720.
25.
Malizia A L, Forse G, Gunn R, Haida A, Melichar J, Poole K, Bateman D, Fahy D, Nutt D, Jones T (1995) A new human (psycho)pharmacology tool: the multiple organs coincidences counter (MOCC). Journal of Psychopharmacology9: 294–306.
26.
Malizia A L, Gunn R N, Wilson S J, Waters S H, Bloomfield P M, Cunningham V J, Nutt D J (1996) Benzodiazepine site pharmacokinetic/ pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo. Neuropharmacology35: 1483–1491.
27.
Malizia A L, Melichar J M, Brown D J, Gunn R N, Reynolds A, Jones T, Nutt D J (1997) Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo. Journal of Psychopharmacology11: 279–281.
28.
Martinez D, Hwang D, Mawlawi O, Slifstein M, Kent J, Simpson N, Parsey R V, Hashimoto T, Huang Y, Shinn A, Van Heertum R, Abi-Dargham A, Caltabiano S, Malizia A, Cowley H, Mann J J, Laruelle M (2001) Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology24: 209–229.
29.
Mesina C T, Boellaard R, van den Heuvel O A, Veltman D J, Jongbloed G, van der Vaart A W, Lammertsma A A (2003) Effects of attenuation correction and reconstruction method on PET activation studies. Neuroimage20: 898–908.
30.
Meyer J H, Wilson A A, Sagrati S, Hussey D, Carella A, Potter W Z, Ginovart N, Spencer E P, Cheok A, Houle S (2004) Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. American Journal of Psychiatry161: 826–835.
31.
Noble E P, Gottschalk L A, Fallon J H, Ritchie T L, Wu J C (1997) D2 dopamine receptor polymorphism and brain regional glucose metabolism. American Journal of Medical Genetics74: 162–166.
32.
Nordstrom A L, Farde L, Halldin C (1992) Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology106: 433–438.
33.
Nordstrom A L, Farde L, Wiesel F A, Forslund K, Pauli S, Halldin C, Uppfeldt G (1993) Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients. Biological Psychiatry33:227–235.
34.
Nordstrom A L, Farde L, Nyberg S, Karlsson P, Halldin C, Sedvall G (1995) D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. American Journal of Psychiatry152: 1444–1449.
35.
Nyberg S, Farde L, Halldin C (1997) Delayed normalization of central D2 dopamine receptor availability after discontinuation of haloperidol decanoate. Preliminary findings. Archives of General Psychiatry54: 953–958.
36.
Nyberg S, Farde L, Halldin C, Dahl M L, Bertilsson L (1995)D2 dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. American Journal of Psychiatry152: 173–178.
37.
Nyberg S, Nordstrom A L, Halldin C, Farde L (1995) Positron emission tomography studies on D2 dopamine receptor occupancy and plasma antipsychotic drug levels in man. International Clinical Psychopharmacology10Suppl 3: 81–85.
38.
Olsson H, Farde L (2001) Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy–a simulation study based on experimental data. Neuroimage14: 936–945.
39.
Olsson H, Farde L (2005) Half-life of receptor occupancy–a meaningless concept. International Journal of Neuropsychopharmacology8: 141–142.
40.
Pohjalainen T, Nagren K, Syvalahti E K, Hietala J (1999) The dopamine D2 receptor 5'-flanking variant, -141C Ins/Del, is not associated with reduced dopamine D2 receptor density in vivo. Pharmacogenetics9: 505–509.
41.
Rabiner E A, Wilkins M R, Turkheimer F, Gunn R N, Udo de Haes J, de Vries M, Grasby P M (2002) 5-Hydroxytryptamine1A receptor occupancy by novel full antagonist 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-d ioxide: a[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) positron emission tomography study in humans. Journal of Pharmacology & Experimental Therapeutics301: 1144–1150.
42.
Schreckenberger M, Lange-Asschenfeld C, Lochmann M, Mann K, Siessmeier T, Buchholz H G, Bartenstein P, Grunder G (2004) The thalamus as the generator and modulator of EEG alpha rhythm: a combined PET/EEG study with lorazepam challenge in humans. Neuroimage22: 637–644.
43.
Shioe K, Ichimiya T, Suhara T, Takano A, Sudo Y, Yasuno F, Hirano M, Shinohara M, Kagami M, Okubo Y, Nankai M, Kanba S (2003) No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET. Synapse48: 184–188.
44.
Slifstein M, Laruelle M (2001) Models and methods for derivation of in vivo neuroreceptor parameters with PET and SPECT reversible radio-tracers. Nuclear Medicine & Biology28: 595–608.
45.
Tauscher-Wisniewski S, Kapur S, Tauscher J, Jones C, Daskalakis Z J, Papatheodorou G, Epstein I, Christensen B K, Zipursky R B (2002) Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade. Journal of Clinical Psychiatry63: 992–997.
46.
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 the single photon emission computer tomography tracer [123I]iomazenil. European Journal of Pharmacology249: 43–51.
47.
Volkow N D, Wang G J, Fowler J S, Logan J, Gatley S J, Hitzemann R, Chen A D, Dewey S L, Pappas N.(1997) Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature386: 830–833.
48.
Volkow N D, Wang G J, Fowler J S, Logan J, Gatley S J, Gifford A, Hitzemann R, Ding Y S, Pappas N (1999) Prediction of reinforcing responses to psychostimulants in humans by brain dopamine D2 receptor levels. American Journal of Psychiatry156: 1440–1443.
49.
Volkow N D, Wang G J, Fowler J S, Logan J, Gatley S J, Wong C, Hitzemann R, Pappas N R (1999) Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. Journal of Pharmacology & Experimental Therapeutics291: 409–415.
50.
Volkow N D, Wang G J, Fowler J S, Gatley S J, Logan J, Ding Y S, Dewey S L, Hitzemann R, Gifford A N, Pappas N R (1999) Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of ‘high’. Journal of Pharmacology & Experimental Therapeutics288: 14–20.
51.
Volkow N D, Chang L, Wang G J, Fowler J S, Franceschi D, Sedler M, Gatley S J, Miller E, Hitzemann R, Ding Y S, Logan J (2001). Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. Journal of Neuroscience21: 9414–9418.
52.
Volkow N D, Wang G J, Ma Y, Fowler J S, Zhu W, Maynard L, Telang F, Vaska P, Ding Y S, Wong C, Swanson J M (2003) Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. Journal of Neuroscience23: 11461–11468.
