Skip to main content
SpringerLink
Log in

The Assay of Enzyme Activity by Positron Emission Tomography

  • Protocol
  • First Online:
Molecular Imaging in the Clinical Neurosciences

Part of the book series: Neuromethods ((NM,volume 71))

Abstract

In a relatively small number of instances, the activity in brain of specific enzymes can be measured with positron emission tomography (PET) using radioactive enzyme substrates in conjunction with compartmental modeling. Thus, the trapping of [11C]-labeled amino acids in brain protein was an early application of PET, which has found particular use in the detection of brain tumors. The most successful PET agent remains the glucose analog [18F]-fluoro-deoxyglucose (FDG), which is trapped in brain as FDG-phosphate, at a rate determined by the local activity of the hexokinase enzyme. The integrity of nigrostriatal dopamine innervations can be assessed with the DOPA decarboxylase tracer [18F]-fluoro-l-DOPA (FDOPA), whereas the rate of serotonin synthesis has been measured in PET studies with α-[14C]-methyl-l-tryptophan. Monoamine oxidase, uniquely, can be assessed in PET studies with suicide substrates such as l-[11C]-deprenyl, where the rate of trapping in living tissue is a function of the local catalytic activity of MAO-B. However, the abundance of MAO-A is most conveniently assessed with [11C]-harmine and other competitor ligands, which bind reversibly to the enzyme. [11C]-PMP and a number of other substrates for acetylcholine esterase have been developed, based on the production in situ of a nondiffusible hydrolysis product. The activity of P-glycoprotein in the blood–brain barrier can be assessed only indirectly, by virtue of increased influx to brain of labeled substrates, following administration of P-glycoprotein inhibitors. Positron-emitting inhibitors of phosphodiesterase enzymes have been described, which should herald the eventual development of a much wider array of tracers targeting signal transduction pathways. Cell proliferation can be detected with [11C]-thymidine and synthetic nucleosides. Very recently, it has become possible to measure the abundance in brain of aromatase, which catalyzes the synthesis of estrogen. In general, the net influx of an enzyme substrate from blood to brain is calculated by linear graphical analysis, whereas individual steps in the non-uptake process can be estimated by compartmental analysis. When trapping of a PET tracer is catalyzed by the enzymatic step, the magnitude of the corresponding rate constant (k 3; min−1) ranges from the lowest useful limit of 0.01 min−1 (α-[14C]-methyl-l-tryptophan) to >0.1 min−1 (l-[11C]-deprenyl, [11C]PMP). Quantification is problematic at the lower end of this range due to low specific signal and also at the high end due to blood flow limiting effects.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Comar D, Cartron J, Maziere M, Marazano C (1976) Labelling and metabolism of methionine-methyl-11 C. Eur J Nucl Med 1:11–14

    PubMed  CAS  Google Scholar 

  2. Christensen HN (1990) Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 70:43–77

    PubMed  CAS  Google Scholar 

  3. Salmon E, Gregoire MC, Delfiore G, Lemaire C, Degueldre C, Franck G, Comar D (1996) Combined study of cerebral glucose metabolism and [11 C]methionine accumulation in probable Alzheimer’s disease using positron emission tomography. J Cereb Blood Flow Metab 16:399–408

    PubMed  CAS  Google Scholar 

  4. Cumming P, Ase A, Kuwabara H, Gjedde A (1998) [3 H]DOPA formed from [3 H]tyrosine in living rat brain is not committed to dopamine synthesis. J Cereb Blood Flow Metab 18:491–499

    PubMed  CAS  Google Scholar 

  5. Bishu S, Schmidt KC, Burlin T, Channing M, Conant S, Huang T, Liu ZH, Qin M, Unterman A, Xia Z, Zametkin A, Herscovitch P, Smith CB (2008) Regional rates of cerebral protein synthesis measured with L-[1-11 C]leucine and PET in conscious, young adult men: normal values, variability, and reproducibility. J Cereb Blood Flow Metab 28:1502–1513

    PubMed  CAS  Google Scholar 

  6. Bustany P, Chatel M, Derlon JM, Darcel F, Sgouropoulos P, Soussaline F, Syrota A (1986) Brain tumor protein synthesis and histological grades: a study by positron emission tomography (PET) with C11-L-Methionine. J Neurooncol 3:397–404

    PubMed  CAS  Google Scholar 

  7. Singhal T, Narayanan TK, Jain V, Mukherjee J, Mantil J (2008) 11 C-L-methionine positron emission tomography in the clinical management of cerebral gliomas. Mol Imaging Biol 10:1–18

    PubMed  Google Scholar 

  8. Narayanan TK, Said S, Mukherjee J, Christian B, Satter M, Dunigan K, Shi B, Jacobs M, Bernstein T, Padma M, Mantil J (2002) A comparative study on the uptake and incorporation of radiolabeled methionine, choline and fluorodeoxyglucose in human astrocytoma. Mol Imaging Biol 4:147–156

    PubMed  CAS  Google Scholar 

  9. Lindner KJ, Hartvig P, Akesson C, Tyrefors N, Sundin A, Langstrom B (1996) Analysis of L-[methyl-11 C]methionine and metabolites in human plasma by an automated solid-phase extraction and a high-performance liquid chromatographic procedure. J Chromatogr B Biomed Appl 679:13–19

    PubMed  CAS  Google Scholar 

  10. Ishiwata K, Vaalburg W, Elsinga PH, Paans AM, Woldring MG (1988) Comparison of L-[1-11 C]methionine and L-methyl-[11 C]methionine for measuring in vivo protein synthesis rates with PET. J Nucl Med 29(8):1419–1427

    PubMed  CAS  Google Scholar 

  11. Ishiwata K, Vaalburg W, Elsinga PH, Paans AM, Woldring MG (1988) Metabolic studies with L-[1-14 C]tyrosine for the investigation of a kinetic model to measure protein synthesis rates with PET. J Nucl Med 29(4):524–529

    PubMed  CAS  Google Scholar 

  12. Coenen HH, Kling P, Stocklin G (1989) Cerebral metabolism of L-[2-18 F]fluorotyrosine, a new PET tracer of protein synthesis. J Nucl Med 30:1367–1372

    PubMed  CAS  Google Scholar 

  13. Wienhard K, Herholz K, Coenen HH, Rudolf J, Kling P, Stocklin G, Heiss WD (1991) Increased amino acid transport into brain tumors measured by PET of L-(2-18 F)fluorotyrosine. J Nucl Med 32:1338–1346

    PubMed  CAS  Google Scholar 

  14. Ramm P, Smith CT (1990) Rates of cerebral protein synthesis are linked to slow wave sleep in the rat. Physiol Behav 48:749–753

    PubMed  CAS  Google Scholar 

  15. Smith CB, Sun Y, Sokoloff L (1995) Effects of aging on regional rates of cerebral protein synthesis in the Sprague-Dawley rat: examination of the influence of recycling of amino acids derived from protein degradation into the precursor pool. Neurochem Int 27:407–416

    PubMed  CAS  Google Scholar 

  16. Hoeksma M, Reijngoud DJ, Pruim J, de Valk HW, Paans AM, van Spronsen FJ (2009) Phenylketonuria: high plasma phenylalanine decreases cerebral protein synthesis. Mol Genet Metab 96:177–182

    PubMed  CAS  Google Scholar 

  17. Bishu S, Schmidt KC, Burlin TV, Channing MA, Horowitz L, Huang T, Liu ZH, Qin M, Vuong BK, Unterman AJ, Xia Z, Zametkin A, Herscovitch P, Quezado Z, Smith CB (2009) Propofol anesthesia does not alter regional rates of cerebral protein synthesis measured with L-[1-(11)C]leucine and PET in healthy male subjects. J Cereb Blood Flow Metab 29:1035–1047

    PubMed  CAS  Google Scholar 

  18. Rolleston FS, Newsholme EA (1967) Effects of fatty acids, ketone bodies, lactate and pyruvate on glucose utilization by guinea-pig cerebral cortex slices. Biochem J 104:519–523

    PubMed  CAS  Google Scholar 

  19. Poulsen PH, Smith DF, Ostergaard L, Danielsen EH, Gee A, Hansen SB, Astrup J, Gjedde A (1997) In vivo estimation of cerebral blood flow, oxygen consumption and glucose metabolism in the pig by [15O]water injection, [15O]oxygen inhalation and dual injections of [18 F]fluorodeoxyglucose. J Neurosci Methods 77:199–209

    PubMed  CAS  Google Scholar 

  20. Brondsted HE, Gjedde A (1988) Measuring brain glucose phosphorylation with labeled glucose. Am J Physiol 254:E443–E448

    PubMed  CAS  Google Scholar 

  21. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14 C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916

    PubMed  CAS  Google Scholar 

  22. Huang SC, Phelps ME, Hoffman EJ, Sideris K, Selin CJ, Kuhl DE (1980) Noninvasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol 238:E69–E82

    PubMed  CAS  Google Scholar 

  23. Souza Ade A, da Silva GS, Velez BS, Santoro AB, Montero-Lomeli M (2010) Glycogen synthesis in brain and astrocytes is inhibited by chronic lithium treatment. Neurosci Lett 482:128–132

    PubMed  Google Scholar 

  24. Gjedde A (1982) Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: a re-examination. Brain Res 257:237–274

    PubMed  CAS  Google Scholar 

  25. Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3:1–7

    PubMed  CAS  Google Scholar 

  26. de Leon MJ, Ferris SH, George AE, Christman DR, Fowler JS, Gentes C, Reisberg B, Gee B, Emmerich M, Yonekura Y, Brodie J, Kricheff II, Wolf AP (1983) Positron emission tomographic studies of aging and Alzheimer disease. AJNR Am J Neuroradiol 4:568–571

    PubMed  Google Scholar 

  27. Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE (1995) A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. J Nucl Med 36:1238–1248

    PubMed  CAS  Google Scholar 

  28. Borghammer P, Cumming P, Aanerud J, Forster S, Gjedde A (2009) Subcortical elevation of metabolism in Parkinson’s disease – a critical reappraisal in the context of global mean normalization. Neuroimage 47:1514–1521

    PubMed  Google Scholar 

  29. Yakushev I, Hammers A, Fellgiebel A, Schmidtmann I, Scheurich A, Buchholz HG, Peters J, Bartenstein P, Lieb K, Schreckenberger M (2009) SPM-based count normalization provides excellent discrimination of mild Alzheimer’s disease and amnestic mild cognitive impairment from healthy aging. Neuroimage 44:43–50

    PubMed  Google Scholar 

  30. Borghammer P, Aanerud J, Gjedde A (2009) Data-driven intensity normalization of PET group comparison studies is superior to global mean normalization. Neuroimage 46:981–988

    PubMed  Google Scholar 

  31. Del Sole A, Clerici F, Chiti A, Lecchi M, Mariani C, Maggiore L, Mosconi L, Lucignani G (2008) Individual cerebral metabolic deficits in Alzheimer’s disease and amnestic mild cognitive impairment: an FDG PET study. Eur J Nucl Med Mol Imaging 35:1357–1366

    PubMed  Google Scholar 

  32. Devanand DP, Mikhno A, Pelton GH, Cuasay K, Pradhaban G, Dileep Kumar JS, Upton N, Lai R, Gunn RN, Libri V, Liu X, van Heertum R, Mann JJ, Parsey RV (2010) Pittsburgh compound B (11 C-PIB) and fluorodeoxyglucose (18 F-FDG) PET in patients with Alzheimer disease, mild cognitive impairment, and healthy controls. J Geriatr Psychiatry Neurol 23:185–198

    PubMed  CAS  Google Scholar 

  33. Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, Pirraglia E, De Santi S, Reisberg B, Wisniewski T, de Leon MJ (2009) FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur J Nucl Med Mol Imaging 36:811–822

    PubMed  CAS  Google Scholar 

  34. Garnett S, Firnau G, Nahmias C, Chirakal R (1983) Striatal dopamine metabolism in living monkeys examined by positron emission tomography. Brain Res 280:169–171

    PubMed  CAS  Google Scholar 

  35. Leenders KL, Poewe WH, Palmer AJ, Brenton DP, Frackowiak RS (1986) Inhibition of L-[18 F]fluorodopa uptake into human brain by amino acids demonstrated by positron emission tomography. Ann Neurol 20:258–262

    PubMed  CAS  Google Scholar 

  36. Cumming P, Hausser M, Martin WR, Grierson J, Adam MJ, Ruth TJ, McGeer EG (1988) Kinetics of in vitro decarboxylation and the in vivo metabolism of 2-18 F- and 6-18 F-fluorodopa in the hooded rat. Biochem Pharmacol 37:247–250

    PubMed  CAS  Google Scholar 

  37. Endres CJ, Swaminathan S, DeJesus OT, Sievert M, Ruoho AE, Murali D, Rommelfanger SG, Holden JE (1997) Affinities of dopamine analogs for monoamine granular and plasma membrane transporters: implications for PET dopamine studies. Life Sci 60:2399–2406

    PubMed  CAS  Google Scholar 

  38. Kumakura Y, Cumming P (2009) PET studies of cerebral levodopa metabolism: a review of clinical findings and modeling approaches. Neuroscientist 15:635–650

    PubMed  CAS  Google Scholar 

  39. Creveling CR, Kirk KL (1985) The effect of ring-fluorination on the rate of O-methylation of dihydroxyphenylalanine (DOPA) by catechol-O-methyltransferase: significance in the development of 18 F-PETT scanning agents. Biochem Biophys Res Commun 130:1123–1131

    PubMed  CAS  Google Scholar 

  40. Boyes BE, Cumming P, Martin WR, McGeer EG (1986) Determination of plasma [18 F]-6-fluorodopa during positron emission tomography: elimination and metabolism in carbidopa treated subjects. Life Sci 39:2243–2252

    PubMed  CAS  Google Scholar 

  41. Cumming P, Boyes BE, Martin WR, Adam M, Ruth TJ, McGeer EG (1987) Altered metabolism of [18 F]-6-fluorodopa in the hooded rat following inhibition of catechol-O-methyltransferase with U-0521. Biochem Pharmacol 36:2527–2531

    PubMed  CAS  Google Scholar 

  42. Dhawan V, Ishikawa T, Patlak C, Chaly T, Robeson W, Belakhlef A, Margouleff C, Mandel F, Eidelberg D (1996) Combined FDOPA and 3OMFD PET studies in Parkinson’s disease. J Nucl Med 37:209–216

    PubMed  CAS  Google Scholar 

  43. Cumming P, Boyes BE, Martin WR, Adam M, Grierson J, Ruth T, McGeer EG (1987) The metabolism of [18 F]6-fluoro-L-3,4-dihydroxyphenylalanine in the hooded rat. J Neurochem 48:601–608

    PubMed  CAS  Google Scholar 

  44. Huang SC, Yu DC, Barrio JR, Grafton S, Melega WP, Hoffman JM, Satyamurthy N, Mazziotta JC, Phelps ME (1991) Kinetics and modeling of L-6-[18 F]fluoro-dopa in human positron emission tomographic studies. J Cereb Blood Flow Metab 11:898–913

    PubMed  CAS  Google Scholar 

  45. Kumakura Y, Danielsen EH, Gjedde A, Vernaleken I, Buchholz HG, Heinz A, Grunder G, Bartenstein P, Cumming P (2010) Elevated [(18)F]FDOPA utilization in the periaqueductal gray and medial nucleus accumbens of patients with early Parkinson’s disease. Neuroimage 49:2933–2939

    PubMed  CAS  Google Scholar 

  46. Kuwabara H, Cumming P, Reith J, Leger G, Diksic M, Evans AC, Gjedde A (1993) Human striatal L-dopa decarboxylase activity estimated in vivo using 6-[18 F]fluoro-dopa and positron emission tomography: error analysis and application to normal subjects. J Cereb Blood Flow Metab 13:43–56

    PubMed  CAS  Google Scholar 

  47. Kuwabara H, Cumming P, Yasuhara Y, Leger GC, Guttman M, Diksic M, Evans AC, Gjedde A (1995) Regional striatal DOPA transport and decarboxylase activity in Parkinson’s disease. J Nucl Med 36:1226–1231

    PubMed  CAS  Google Scholar 

  48. Sawle GV, Wroe SJ, Lees AJ, Brooks DJ, Frackowiak RS (1992) The identification of presymptomatic parkinsonism: clinical and [18 F]dopa positron emission tomography studies in an Irish kindred. Ann Neurol 32:609–617

    PubMed  CAS  Google Scholar 

  49. Morrish PK, Rakshi JS, Bailey DL, Sawle GV, Brooks DJ (1998) Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18 F]dopa PET. J Neurol Neurosurg Psychiatry 64:314–319

    PubMed  CAS  Google Scholar 

  50. Rakshi JS, Pavese N, Uema T, Ito K, Morrish PK, Bailey DL, Brooks DJ (2002) A comparison of the progression of early Parkinson’s disease in patients started on ropinirole or L-dopa: an 18 F-dopa PET study. J Neural Transm 109:1433–1443

    PubMed  CAS  Google Scholar 

  51. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F, Bachneff S, Cumming P, Diksic M, Dyve SE, Etienne P, Evans AC, Lal S, Shevell M, Savard G, Wong DF, Chouinard G, Gjedde A (1994) Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci USA 91:11651–11654

    PubMed  CAS  Google Scholar 

  52. Nozaki S, Kato M, Takano H, Ito H, Takahashi H, Arakawa R, Okumura M, Fujimura Y, Matsumoto R, Ota M, Takano A, Otsuka A, Yasuno F, Okubo Y, Kashima H, Suhara T (2009) Regional dopamine synthesis in patients with schizophrenia using L-[beta-11 C]DOPA PET. Schizophr Res 108:78–84

    PubMed  Google Scholar 

  53. Kumakura Y, Cumming P, Vernaleken I, Buchholz HG, Siessmeier T, Heinz A, Kienast T, Bartenstein P, Grunder G (2007) Elevated [18 F]fluorodopamine turnover in brain of patients with schizophrenia: an [18 F]fluorodopa/positron emission tomography study. J Neurosci 27:8080–8087

    PubMed  CAS  Google Scholar 

  54. Hagberg GE, Torstenson R, Marteinsdottir I, Fredrikson M, Langstrom B, Blomqvist G (2002) Kinetic compartment modeling of [11 C]-5-hydroxy-L-tryptophan for positron emission tomography assessment of serotonin synthesis in human brain. J Cereb Blood Flow Metab 22:1352–1366

    PubMed  CAS  Google Scholar 

  55. Diksic M, Tohyama Y, Takada A (2000) Brain net unidirectional uptake of alpha-[14c]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp. Neurochem Res 25:1537–1546

    PubMed  CAS  Google Scholar 

  56. Shoaf SE, Carson RE, Hommer D, Williams WA, Higley JD, Schmall B, Herscovitch P, Eckelman WC, Linnoila M (2000) The suitability of [11 C]-alpha-methyl-L-tryptophan as a tracer for serotonin synthesis: studies with dual administration of [11 C] and [14 C] labeled tracer. J Cereb Blood Flow Metab 20:244–252

    PubMed  CAS  Google Scholar 

  57. Leyton M, Diksic M, Benkelfat C (2005) Brain regional alpha-[11 C]methyl-L-tryptophan trapping correlates with post-mortem tissue serotonin content and [11 C]5-hydroxytryptophan accumulation. Int J Neuropsychopharmacol 8:633–634

    PubMed  CAS  Google Scholar 

  58. Muzik O, Chugani DC, Chakraborty P, Mangner T, Chugani HT (1997) Analysis of [C-11]alpha-methyl-tryptophan kinetics for the estimation of serotonin synthesis rate in vivo. J Cereb Blood Flow Metab 17:659–669

    PubMed  CAS  Google Scholar 

  59. Sakai Y, Dobson C, Diksic M, Aube M, Hamel E (2008) Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology 70:431–439

    PubMed  CAS  Google Scholar 

  60. Juhasz C, Chugani DC, Muzik O, Shah A, Asano E, Mangner TJ, Chakraborty PK, Sood S, Chugani HT (2003) Alpha-methyl-L-tryptophan PET detects epileptogenic cortex in children with intractable epilepsy. Neurology 60:960–968

    PubMed  CAS  Google Scholar 

  61. Fedi M, Reutens DC, Andermann F, Okazawa H, Boling W, White C, Dubeau F, Nakai A, Gross DW, Andermann E, Diksic M (2003) Alpha-[11 C]-methyl-L-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency. Epilepsy Res 52:203–213

    PubMed  Google Scholar 

  62. Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S, Nakai A, Debonnel G, Blier P, Benkelfat C (2004) Measurement of brain regional alpha-[11 C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 61:556–563

    PubMed  CAS  Google Scholar 

  63. Leyton M, Paquette V, Gravel P, Rosa-Neto P, Weston F, Diksic M, Benkelfat C (2006) alpha-[11 C]Methyl-L-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters. Eur Neuropsychopharmacol 16:220–223

    PubMed  CAS  Google Scholar 

  64. Berney A, Nishikawa M, Benkelfat C, Debonnel G, Gobbi G, Diksic M (2008) An index of 5-HT synthesis changes during early antidepressant treatment: alpha-[11 C]methyl-L-tryptophan PET study. Neurochem Int 52:701–708

    PubMed  CAS  Google Scholar 

  65. Kitahama K, Maeda T, Denney RM, Jouvet M (1994) Monoamine oxidase: distribution in the cat brain studied by enzyme- and immunohistochemistry: recent progress. Prog Neurobiol 42:53–78

    PubMed  CAS  Google Scholar 

  66. Nakamura S, Vincent SR (1986) Histochemistry of MPTP oxidation in the rat brain: sites of synthesis of the parkinsonism-inducing toxin MPP+. Neurosci Lett 65:321–325

    PubMed  CAS  Google Scholar 

  67. Moerlein SM, Stocklin G, Pawlik G, Wienhard K, Heiss WD (1986) Regional cerebral pharmacokinetics of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as examined by positron emission tomography in a baboon is altered by tranylcypromine. Neurosci Lett 66:205–209

    PubMed  CAS  Google Scholar 

  68. Hartvig P, Larsson BS, Lindberg BS, Oreland L, Gullberg P, Langstrom B, Rimland A, Lundqvist H, Malmborg P, Lindquist NG (1986) Influence of monoamine oxidase inhibitors and a dopamine uptake blocker on the distribution of 11 C-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 11 C-MPTP, in the head of the rhesus monkey. Acta Neurol Scand 74:10–16

    PubMed  CAS  Google Scholar 

  69. Fowler JS, MacGregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, Christman D, Logan J, Smith M, Sachs H et al (1987) Mapping human brain monoamine oxidase A and B with 11 C-labeled suicide inactivators and PET. Science 235:481–485

    PubMed  CAS  Google Scholar 

  70. Fowler JS, Wolf AP, MacGregor RR, Dewey SL, Logan J, Schlyer DJ, Langstrom B (1988) Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J Neurochem 51:1524–1534

    PubMed  CAS  Google Scholar 

  71. Fowler JS, Wang GJ, Logan J, Xie S, Volkow ND, MacGregor RR, Schlyer DJ, Pappas N, Alexoff DL, Patlak C et al (1995) Selective reduction of radiotracer trapping by deuterium substitution: comparison of carbon-11-L-deprenyl and carbon-11-deprenyl-D2 for MAO B mapping. J Nucl Med 36:1255–1262

    PubMed  CAS  Google Scholar 

  72. Kumlien E, Nilsson A, Hagberg G, Langstrom B, Bergstrom M (2001) PET with 11 C-deuterium-deprenyl and 18 F-FDG in focal epilepsy. Acta Neurol Scand 103:360–366

    PubMed  CAS  Google Scholar 

  73. Fowler JS, Logan J, Ding YS, Franceschi D, Wang GJ, Volkow ND, Pappas N, Schlyer D, Gatley SJ, Alexoff D, Felder C, Biegon A, Zhu W (2001) Non-MAO A binding of clorgyline in white matter in human brain. J Neurochem 79:1039–1046

    PubMed  CAS  Google Scholar 

  74. Bergstrom M, Westerberg G, Langstrom B (1997) 11 C-harmine as a tracer for monoamine oxidase A (MAO-A): in vitro and in vivo studies. Nucl Med Biol 24:287–293

    PubMed  CAS  Google Scholar 

  75. Bergstrom M, Westerberg G, Nemeth G, Traut M, Gross G, Greger G, Muller-Peltzer H, Safer A, Eckernas SA, Grahner A, Langstrom B (1997) MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography. Eur J Clin Pharmacol 52:121–128

    PubMed  CAS  Google Scholar 

  76. Hirvonen J, Kailajarvi M, Haltia T, Koskimies S, Nagren K, Virsu P, Oikonen V, Sipila H, Ruokoniemi P, Virtanen K, Scheinin M, Rinne JO (2009) Assessment of MAO-B occupancy in the brain with PET and [11 C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther 85:506–512

    PubMed  CAS  Google Scholar 

  77. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, MacGregor R, Alexoff D, Wolf AP, Warner D, Cilento R, Zezulkova I (1998) Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J Addict Dis 17:23–34

    PubMed  CAS  Google Scholar 

  78. Fowler JS, Wang GJ, Volkow ND, Franceschi D, Logan J, Pappas N, Shea C, MacGregor RR, Garza V (1999) Smoking a single cigarette does not produce a measurable reduction in brain MAO B in non-smokers. Nicotine Tob Res 1:325–329

    PubMed  CAS  Google Scholar 

  79. Fowler JS, Volkow ND, Wang GJ, Pappas N, Logan J, Shea C, Alexoff D, MacGregor RR, Schlyer DJ, Zezulkova I, Wolf AP (1996) Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci USA 93:14065–14069

    PubMed  CAS  Google Scholar 

  80. Leroy C, Bragulat V, Berlin I, Gregoire MC, Bottlaender M, Roumenov D, Dolle F, Bourgeois S, Penttila J, Artiges E, Martinot JL, Trichard C (2009) Cerebral monoamine oxidase A inhibition in tobacco smokers confirmed with PET and [11 C]befloxatone. J Clin Psychopharmacol 29:86–88

    PubMed  CAS  Google Scholar 

  81. Pedersen K, Simonsen M, Ostergaard SD, Munk OL, Rosa-Neto P, Olsen AK, Jensen SB, Moller A, Cumming P (2007) Mapping the amphetamine-evoked changes in [11 C]raclopride binding in living rat using small animal PET: modulation by MAO-inhibition. Neuroimage 35:38–46

    PubMed  Google Scholar 

  82. Jensen SB, Olsen AK, Pedersen K, Cumming P (2006) Effect of monoamine oxidase inhibition on amphetamine-evoked changes in dopamine receptor availability in the living pig: a dual tracer PET study with [11 C]harmine and [11 C]raclopride. Synapse 59:427–434

    PubMed  CAS  Google Scholar 

  83. Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, Young T, Praschak-Rieder N, Wilson AA, Houle S (2006) Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry 63:1209–1216

    PubMed  CAS  Google Scholar 

  84. Meyer JH, Wilson AA, Sagrati S, Miler L, Rusjan P, Bloomfield PM, Clark M, Sacher J, Voineskos AN, Houle S (2009) Brain monoamine oxidase A binding in major depressive disorder: relationship to selective serotonin reuptake inhibitor treatment, recovery, and recurrence. Arch Gen Psychiatry 66:1304–1312

    PubMed  Google Scholar 

  85. Sacher J, Wilson AA, Houle S, Rusjan P, Hassan S, Bloomfield PM, Stewart DE, Meyer JH (2010) Elevated brain monoamine oxidase A binding in the early postpartum period. Arch Gen Psychiatry 67:468–474

    PubMed  Google Scholar 

  86. Macwhorter SE, Baldwin RM (1991) Synthesis and biodistribution of 123I N-(2-aminoethyl)-5-iodo-2-pyridinecarboxamide (Ro 43-0463), a monoamine oxidase B inhibitor. Int J Rad Appl Instrum B 18:563–564

    PubMed  CAS  Google Scholar 

  87. Blauenstein P, Remy N, Buck A, Ametamey S, Haberli M, Schubiger PA (1998) In vivo properties of N-(2-aminoethyl)-5-halogeno-2-pyridinecarboxamide 18 F- and 123I-labelled reversible inhibitors of monoamine oxidase B. Nucl Med Biol 25:47–52

    PubMed  CAS  Google Scholar 

  88. Bernard S, Fuseau C, Schmid L, Milcent R, Crouzel C (1996) Synthesis and in vivo studies of a specific monoamine oxidase B inhibitor: 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)- 1,3,4-oxadiazol-[11 C]-2(3 H)-one. Eur J Nucl Med 23:150–156

    PubMed  CAS  Google Scholar 

  89. Saba W, Valette H, Peyronneau MA, Bramoulle Y, Coulon C, Curet O, George P, Dolle F, Bottlaender M (2010) [(11)C]SL25.1188, a new reversible radioligand to study the monoamine oxidase type B with PET: preclinical characterisation in nonhuman primate. Synapse 64:61–69

    PubMed  CAS  Google Scholar 

  90. Tavitian B, Pappata S, Planas AM, Jobert A, Bonnot-Lours S, Crouzel C, DiGiamberardino L (1993) In vivo visualization of acetylcholinesterase with positron emission tomography. Neuroreport 4:535–538

    PubMed  CAS  Google Scholar 

  91. Tavitian B, Pappata S, Bonnot-Lours S, Prenant C, Jobert A, Crouzel C, Di Giamberardino L (1993) Positron emission tomography study of [11 C]methyl-tetrahydroaminoacridine (methyl-tacrine) in baboon brain. Eur J Pharmacol 236:229–238

    PubMed  CAS  Google Scholar 

  92. De Vos F, Santens P, Vermeirsch H, Dewolf I, Dumont F, Slegers G, Dierckx RA, De Reuck J (2000) Pharmacological evaluation of [11 C]donepezil as a tracer for visualization of acetylcholinesterase by PET. Nucl Med Biol 27:745–747

    PubMed  Google Scholar 

  93. Kilbourn MR, Snyder SE, Sherman PS, Kuhl DE (1996) In vivo studies of acetylcholinesterase activity using a labeled substrate, N-[11 C]methylpiperdin-4-yl propionate ([11 C]PMP). Synapse 22:123–131

    PubMed  CAS  Google Scholar 

  94. Koeppe RA, Frey KA, Snyder SE, Meyer P, Kilbourn MR, Kuhl DE (1999) Kinetic modeling of N-[11 C]methylpiperidin-4-yl propionate: alternatives for analysis of an irreversible positron emission tomography trace for measurement of acetylcholinesterase activity in human brain. J Cereb Blood Flow Metab 19:1150–1163

    PubMed  CAS  Google Scholar 

  95. Tanaka N, Fukushi K, Shinotoh H, Nagatsuka S, Namba H, Iyo M, Aotsuka A, Ota T, Tanada S, Irie T (2001) Positron emission tomographic measurement of brain acetylcholinesterase activity using N-[(11)C]methylpiperidin-4-yl acetate without arterial blood sampling: methodology of shape analysis and its diagnostic power for Alzheimer’s disease. J Cereb Blood Flow Metab 21:295–306

    PubMed  CAS  Google Scholar 

  96. Herholz K, Lercher M, Wienhard K, Bauer B, Lenz O, Heiss WD (2001) PET measurement of cerebral acetylcholine esterase activity without blood sampling. Eur J Nucl Med 28:472–477

    PubMed  CAS  Google Scholar 

  97. Kuhl DE, Koeppe RA, Minoshima S, Snyder SE, Ficaro EP, Foster NL, Frey KA, Kilbourn MR (1999) In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer’s disease. Neurology 52:691–699

    PubMed  CAS  Google Scholar 

  98. Iyo M, Namba H, Fukushi K, Shinotoh H, Nagatsuka S, Suhara T, Sudo Y, Suzuki K, Irie T (1997) Measurement of acetylcholinesterase by positron emission tomography in the brains of healthy controls and patients with Alzheimer’s disease. Lancet 349:1805–1809

    PubMed  CAS  Google Scholar 

  99. Shiraishi T, Kikuchi T, Fukushi K, Shinotoh H, Nagatsuka S, Tanaka N, Ota T, Sato K, Hirano S, Tanada S, Iyo M, Irie T (2005) Estimation of plasma IC50 of donepezil hydrochloride for brain acetylcholinesterase inhibition in monkey using N-[11 C]methylpiperidin-4-yl acetate ([11 C]MP4A) and PET. Neuropsychopharmacology 30:2154–2161

    PubMed  CAS  Google Scholar 

  100. Ota T, Shinotoh H, Fukushi K, Kikuchi T, Sato K, Tanaka N, Shimada H, Hirano S, Miyoshi M, Arai H, Suhara T, Irie T (2010) Estimation of plasma IC50 of donepezil for cerebral acetylcholinesterase inhibition in patients with Alzheimer disease using positron emission tomography. Clin Neuropharmacol 33:74–78

    PubMed  CAS  Google Scholar 

  101. Kaasinen V, Nagren K, Jarvenpaa T, Roivainen A, Yu M, Oikonen V, Kurki T, Rinne JO (2002) Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer’s disease. J Clin Psychopharmacol 22:615–620

    PubMed  CAS  Google Scholar 

  102. Tsukada H, Nishiyama S, Fukumoto D, Ohba H, Sato K, Kakiuchi T (2004) Effects of acute acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: functional imaging of the conscious monkey brain using animal PET in combination with microdialysis. Synapse 52:1–10

    PubMed  CAS  Google Scholar 

  103. Kadir A, Darreh-Shori T, Almkvist O, Wall A, Grut M, Strandberg B, Ringheim A, Eriksson B, Blomquist G, Langstrom B, Nordberg A (2008) PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiol Aging 29:1204–1217

    PubMed  CAS  Google Scholar 

  104. Herholz K, Weisenbach S, Zundorf G, Lenz O, Schroder H, Bauer B, Kalbe E, Heiss WD (2004) In vivo study of acetylcholine esterase in basal forebrain, amygdala, and cortex in mild to moderate Alzheimer disease. Neuroimage 21:136–143

    PubMed  CAS  Google Scholar 

  105. Darreh-Shori T, Kadir A, Almkvist O, Grut M, Wall A, Blomquist G, Eriksson B, Langstrom B, Nordberg A (2008) Inhibition of acetylcholinesterase in CSF versus brain assessed by 11 C-PMP PET in AD patients treated with galantamine. Neurobiol Aging 29:168–184

    PubMed  CAS  Google Scholar 

  106. Roivainen A, Rinne J, Virta J, Jarvenpaa T, Salomaki S, Yu M, Nagren K (2004) Biodistribution and blood metabolism of 1-11 C-methyl-4-piperidinyl n-butyrate in humans: an imaging agent for in vivo assessment of butyrylcholinesterase activity with PET. J Nucl Med 45:2032–2039

    PubMed  CAS  Google Scholar 

  107. Darreh-Shori T, Forsberg A, Modiri N, Andreasen N, Blennow K, Kamil C, Ahmed H, Almkvist O, Langstrom B, Nordberg A (2011) Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer’s disease in the brain in vivo. Neurobiol Aging 32(12):2320.e15–32

    CAS  Google Scholar 

  108. Elsinga PH, Hendrikse NH, Bart J, Vaalburg W, van Waarde A (2004) PET Studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des 10:1493–1503

    PubMed  CAS  Google Scholar 

  109. Hendrikse NH, Schinkel AH, de Vries EG, Fluks E, Van der Graaf WT, Willemsen AT, Vaalburg W, Franssen EJ (1998) Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography. Br J Pharmacol 124:1413–1418

    PubMed  CAS  Google Scholar 

  110. Takano A, Kusuhara H, Suhara T, Ieiri I, Morimoto T, Lee YJ, Maeda J, Ikoma Y, Ito H, Suzuki K, Sugiyama Y (2006) Evaluation of in vivo P-glycoprotein function at the blood-brain barrier among MDR1 gene polymorphisms by using 11 C-verapamil. J Nucl Med 47:1427–1433

    PubMed  CAS  Google Scholar 

  111. Bauer M, Karch R, Neumann F, Abrahim A, Wagner CC, Kletter K, Muller M, Zeitlinger M, Langer O (2009) Age dependency of cerebral P-gp function measured with (R)-[11 C]verapamil and PET. Eur J Clin Pharmacol 65:941–946

    PubMed  CAS  Google Scholar 

  112. Bartels AL, Willemsen AT, Kortekaas R, de Jong BM, de Vries R, de Klerk O, van Oostrom JC, Portman A, Leenders KL (2008) Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSA. J Neural Transm 115:1001–1009

    PubMed  CAS  Google Scholar 

  113. Lam FC, Liu R, Lu P, Shapiro AB, Renoir JM, Sharom FJ, Reiner PB (2001) beta-Amyloid efflux mediated by p-glycoprotein. J Neurochem 76:1121–1128

    PubMed  CAS  Google Scholar 

  114. Langer O, Bauer M, Hammers A, Karch R, Pataraia E, Koepp MJ, Abrahim A, Luurtsema G, Brunner M, Sunder-Plassmann R, Zimprich F, Joukhadar C, Gentzsch S, Dudczak R, Kletter K, Muller M, Baumgartner C (2007) Pharmacoresistance in epilepsy: a pilot PET study with the P-glycoprotein substrate R-[(11)C]verapamil. Epilepsia 48:1774–1784

    PubMed  CAS  Google Scholar 

  115. la Fougere C, Boning G, Bartmann H, Wangler B, Nowak S, Just T, Wagner E, Winter P, Rominger A, Forster S, Gildehaus FJ, Rosa-Neto P, Minuzzi L, Bartenstein P, Potschka H, Cumming P (2010) Uptake and binding of the serotonin 5-HT1A antagonist [18 F]-MPPF in brain of rats: effects of the novel P-glycoprotein inhibitor tariquidar. Neuroimage 49:1406–1415

    PubMed  Google Scholar 

  116. Bartmann H, Fuest C, la Fougere C, Xiong G, Just T, Schlichtiger J, Winter P, Boning G, Wangler B, Pekcec A, Soerensen J, Bartenstein P, Cumming P, Potschka H (2010) Imaging of P-glycoprotein-mediated pharmacoresistance in the hippocampus: proof-of-concept in a chronic rat model of temporal lobe epilepsy. Epilepsia 51(9):1780–1790

    PubMed  CAS  Google Scholar 

  117. Kreisl WC, Liow JS, Kimura N, Seneca N, Zoghbi SS, Morse CL, Herscovitch P, Pike VW, Innis RB (2010) P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11 C-N-desmethyl-loperamide. J Nucl Med 51:559–566

    PubMed  CAS  Google Scholar 

  118. Bauer F, Kuntner C, Bankstahl JP, Wanek T, Bankstahl M, Stanek J, Mairinger S, Dorner B, Loscher W, Muller M, Erker T, Langer O (2010) Synthesis and in vivo evaluation of [11 C]tariquidar, a positron emission tomography radiotracer based on a third-generation P-glycoprotein inhibitor. Bioorg Med Chem 18:5489–5497

    PubMed  CAS  Google Scholar 

  119. Shields AF, Lim K, Grierson J, Link J, Krohn KA (1990) Utilization of labeled thymidine in DNA synthesis: studies for PET. J Nucl Med 31:337–342

    PubMed  CAS  Google Scholar 

  120. Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, Obradovich JE, Muzik O, Mangner TJ (1998) Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 4:1334–1336

    PubMed  CAS  Google Scholar 

  121. Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, Satyamurthy N, Pope W, Lai A, Phelps ME, Cloughesy T (2007) Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18 F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 25:4714–4721

    PubMed  CAS  Google Scholar 

  122. Ullrich R, Backes H, Li H, Kracht L, Miletic H, Kesper K, Neumaier B, Heiss WD, Wienhard K, Jacobs AH (2008) Glioma proliferation as assessed by 3′-fluoro-3′-deoxy-L-thymidine positron emission tomography in patients with newly diagnosed high-grade glioma. Clin Cancer Res 14:2049–2055

    PubMed  CAS  Google Scholar 

  123. Blasberg RG, Tjuvajev JG (1999) Herpes simplex virus thymidine kinase as a marker/reporter gene for PET imaging of gene therapy. Q J Nucl Med 43:163–169

    PubMed  CAS  Google Scholar 

  124. Brust P, Haubner R, Friedrich A, Scheunemann M, Anton M, Koufaki ON, Hauses M, Noll S, Noll B, Haberkorn U, Schackert G, Schackert HK, Avril N, Johannsen B (2001) Comparison of [18 F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression. Eur J Nucl Med 28:721–729

    PubMed  CAS  Google Scholar 

  125. Azcoitia I, Yague JG, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147

    PubMed  CAS  Google Scholar 

  126. Sasano H, Takashashi K, Satoh F, Nagura H, Harada N (1998) Aromatase in the human central nervous system. Clin Endocrinol (Oxf) 48:325–329

    CAS  Google Scholar 

  127. Takahashi K, Bergstrom M, Frandberg P, Vesstrom EL, Watanabe Y, Langstrom B (2006) Imaging of aromatase distribution in rat and rhesus monkey brains with [11 C]vorozole. Nucl Med Biol 33:599–605

    PubMed  CAS  Google Scholar 

  128. Biegon A, Kim SW, Alexoff DL, Jayne M, Carter P, Hubbard B, King P, Logan J, Muench L, Pareto D, Schlyer D, Shea C, Telang F, Wang GJ, Xu Y, Fowler JS (2010) Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11 C]vorozole. Synapse 64:801–807

    PubMed  CAS  Google Scholar 

  129. Biegon A, Kim SW, Logan J, Hooker JM, Muench L, Fowler JS (2010) Nicotine blocks brain estrogen synthase (aromatase): in vivo positron emission tomography studies in female baboons. Biol Psychiatry 67:774–777

    PubMed  CAS  Google Scholar 

  130. Ito H, Naganawa M, Seki C, Takano H, Kanno I, Suhara T (2012) Quantification of neuroreceptors and neurotransporters. Neuromethods DOI 10.1007/7657_2012_44

Download references

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, Ludwig-Maximilians-Universität München, München, Germany

    Paul Cumming

  2. Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Neil Vasdev

Authors
  1. Paul Cumming
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil Vasdev
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. , Dept. of Psychiatry, Psychotherapy,, RWTH Aachen University, Pauwelsstr. 30, Aachen, 52074, Germany

    Gerhard Gründer

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media New York

About this protocol

Cite this protocol

Cumming, P., Vasdev, N. (2012). The Assay of Enzyme Activity by Positron Emission Tomography. In: Gründer, G. (eds) Molecular Imaging in the Clinical Neurosciences. Neuromethods, vol 71. Humana Press, Totowa, NJ. https://doi.org/10.1007/7657_2012_53

Download citation

  • DOI: https://doi.org/10.1007/7657_2012_53

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-988-4

  • Online ISBN: 978-1-61779-989-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation