Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
EJNMMI Research
Published in: EJNMMI Research 1/2012

Open Access 01-12-2012 | Original research

Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects

Authors: Aurelija Jučaite, Zsolt Cselényi, Annie Arvidsson, Gabrielle Åhlberg, Per Julin, Katarina Varnäs, Per Stenkrona, Jan Andersson, Christer Halldin, Lars Farde

Published in: EJNMMI Research | Issue 1/2012

Login to get access

Abstract

Background

Positron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented. In the present test-retest study, we examine the characteristics of [11C](R)-PK11195 binding in detail, using the classical compartment analysis with a metabolite-corrected arterial input function.

Methods

[11C](R)-PK11195 binding was examined in six control subjects at two separate occasions, 6 weeks apart. Results of one-tissue and two-tissue compartment models (1TCM, 2TCM) were compared using the Akaike criteria and F-statistics. The reproducibility of binding potential (BP ND) estimates was evaluated by difference in measurements (error in percent) and intraclass correlation coefficients (ICCs).

Results

[11C](R)-PK11195 binding could be described by 2TCM which was the preferred model. Measurement error (in percent) indicated good reproducibility in large brain regions (mean error: whole brain 4%, grey matter 5%), but not in smaller subcortical regions (putamen 25%, caudate 55%). The ICC values were moderate to low, highest for the white matter (0.73), whole brain and thalamus (0.57), and cortical grey matter (0.47). Sizeable [11C](R)-PK11195 BP ND could be identified throughout the human brain (range 1.11 to 2.21).

Conclusions

High intra-subject variability of [11C](R)-PK11195 binding limits longitudinal monitoring of TSPO changes. The interpretation of [11C](R)-PK11195 binding by 2TCM suggests that the presence of specific binding to TSPO cannot be excluded at physiological conditions.
Appendix
Available only for authorised users
Literature
1.
Doble A, Malgouris C, Daniel M, Daniel N, Imbault F, Basbaum A, Uzan A, Guérémy C, Le Fur G: Labelling of peripheral-type benzodiazepine binding sites in human brain with [3 H]PK 11195: anatomical and subcellular distribution. Brain Res Bull 1987, 18: 49–61.PubMedCrossRef
2.
Cosenza-Nashat M, Zhao ML, Suh HS, Morgan J, Natividad R, Morgello S, Lee SC: Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 2009, 35: 306–328.PubMedCentralPubMedCrossRef
3.
Le Fur G, Perrier ML, Vaucher N, Imbault F, Flamier A, Benavides J, Uzan A, Renault C, Dubroeucq MC, Gueremy C: Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies. Life Sci 1983, 32: 1839–1847.PubMedCrossRef
4.
Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M: Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006, 27: 402–409.PubMedCrossRef
5.
Benavides J, Malgouris C, Imbault F, Begassat F, Uzan A, Renault C, Dubroeucq MC, Gueremy C, Le Fur G: "Peripheral type" benzodiazepine binding sites in rat adrenals: binding studies with [3 H]PK 11195 and autoradiographic localization. Arch Int Pharmacodyn Ther 1983, 266: 38–49.PubMed
6.
Kumlien E, Hilton-Brown P, Spännare B, Gillberg PG: In vitro quantitative autoradiography of [3 H]-L-deprenyl and [3 H]-PK 11195 binding sites in human epileptic hippocampus. Epilepsia 1992, 33: 610–617.PubMedCrossRef
7.
Sitte HH, Wanschitz J, Budka H, Berger ML: Autoradiography with [3 H]PK11195 of spinal tract degeneration in amyotrophic lateral sclerosis. Acta Neuropathol 2001, 101: 75–78.PubMed
8.
Venneti S, Lopresti BJ, Wiley CA: The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 2006, 80: 308–322.PubMedCentralPubMedCrossRef
9.
Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, Gerhard A, Hinz R, Tai YF, Brooks DJ: Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J Nucl Med 2007, 48: 158–167.PubMed
10.
Camsonne R, Crouzel C, Comar D, Maziere M, Prenant C, Sastre J, Moulin MA, Syrota A: Synthesis of N-(C-11) methyl, N-(methyl-1 propyl), (chloro-2 phenyl)-1 isoquinoleine carboxamide-3 (Pk-11195): a new ligand for peripheral benzodiazepine receptors. J Labelled Compounds and Radiopharm 1984, 21: 985–991.CrossRef
11.
Andersson J, Truong P, Halldin C: In-target produced [11C]methane: increased specific radioactivity. Appl Radiat Isot 2009, 67: 106–110.PubMedCrossRef
12.
Lindolm TL, Botes L, Engman E-L, Frank A, Jonsson T, Svensson L, Julin P: Parallel imaging: is GRAPPA a useful acquisition tool for MR imaging intended for volumetric brain analysis? BMC Med Imaging 2009, 9: 15.CrossRef
13.
Farde L, Eriksson L, Blomquist G, Halldin C: Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET-a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 1989, 9: 696–708.PubMedCrossRef
14.
Halldin C, Swahn CG, Farde L, Sedvall G: PET for Drug Development and Evaluation. In Radioligand disposition and metabolism. Edited by: Comar D. Alphen aan den Rijn: Kluwer Academic Publishers; 1995:55–65.
15.
Wu S, Ogden RT, Mann JJ, Parsey RV: Optimal metabolite curve fitting for kinetic modeling of 11C-WAY-100635. J Nucl Med 2007, 48: 926–931.PubMedCrossRef
16.
Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE: Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 1991, 11: 735–744.PubMedCrossRef
17.
Kety SS: The theory and applications of the exchange of inert gas at the lungs and tissues. Pharmacol Rev 1951, 3: 1–41.PubMed
18.
Mintun M, Raichle M, Kilbourn M, Wooten G, Welch M: A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 1984, 15: 217–227.PubMedCrossRef
19.
Farde L, Ito H, Swahn CG, Pike VW, Halldin C: Quantitative analyses of carbonylcarbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med 1998, 39: 1965–1971.PubMed
20.
Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE: Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007, 27: 1533–1539.PubMedCrossRef
21.
Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, Frackowiak RS: Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 1996, 16: 42–52.PubMedCrossRef
22.
Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schyler DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ: Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990, 10: 740–747.PubMedCrossRef
23.
Akaike H: A new look at the statistical model identification. IEEE Trans Autom Control 1974, 19: 716–723.CrossRef
24.
Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BN, Luurtsema G, Windhorst AD, Lammertsma AA: Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J Cereb Blood Flow Metab 2005, 25: 842–851.PubMedCrossRef
25.
van Berckel BN, Bossong MG, Boellaard R, Kloet R, Schuitemaker A, Caspers E, Luurtsema G, Windhorst AD, Cahn W, Lammertsma AA, Kahn RS: Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study. Biol Psychiatry 2008, 64: 820–822.PubMedCrossRef
26.
Owen DR, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, Innis RB, Pike VW, Reynolds R, Matthews PM, Parker CA: Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 2011, 52: 24–32.PubMedCentralPubMedCrossRef
27.
Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP: An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood FlowMetab 2012, 32: 1–5.CrossRef
28.
Benavides J, Cornu P, Dennis T, Dubois A, Hauw JJ, MacKenzie ET, Sazdovitch V, Scatton B: Imaging of human brain lesions with an omega 3 site radioligand. Ann Neurol 1988, 24: 708–712.PubMedCrossRef
29.
Banati RB, Myers R, Kreutzberg GW: PK ('peripheral benzodiazepine')-binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3 H]PK11195 binding to activated microglia. J Neurocytol 1997, 26: 77–82.PubMedCrossRef
30.
Doorduin J, de Vries EF, Willemsen AT, de Groot JC, Dierckx RA, Klein HC: Neuroinflammation in schizophrenia-related psychosis: a PET study. J Nucl Med 2009, 50: 1801–1807.PubMedCrossRef
31.
Rao VL, Butterworth RF: Characterization of binding sites for the omega3 receptor ligands [3 H]PK11195 and [3 H]RO5–4864 in human brain. Eur J Pharmacol 1997, 340: 89–99.PubMedCrossRef
32.
Hall H, Köhler C, Gawell L, Farde L, Sedvall G: Raclopride, a new selective ligand for the dopamine-D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 1988, 12: 559–568.PubMedCrossRef
33.
Hall H, Lundkvist C, Halldin C, Farde L, Pike VW, McCarron JA, Fletcher A, Cliffe IA, Barf T, Wikström H, Sedvall G: Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3 H]WAY-100635 and [11C]way-100635. Brain Res 1997, 745: 96–108.PubMedCrossRef
34.
Fletcher A, Cliffe IA, Dourish CT: Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents. Trends Pharmacol Sci 1993, 14: 41–48.PubMedCrossRef
35.
Petit-Taboué MC, Baron JC, Barré L, Travère JM, Speckel D, Camsonne R, MacKenzie ET: Brain kinetics and specific binding of [11C]PK 11195 to omega 3 sites in baboons: positron emission tomography study. Eur J Pharmacol 1991, 200: 347–351.PubMedCrossRef
36.
Maeda J, Suhara T, Zhang MR, Okauchi T, Yasuno F, Ikoma Y, Inaji M, Nagai Y, Takano A, Obayashi S, Suzuki K: Novel peripheral benzodiazepine receptor ligand [11C]DAA1106 for PET: an imaging tool for glial cells in the brain. Synapse 2004, 52: 283–291.PubMedCrossRef
37.
Kreisl WC, Fujita M, Fujimura Y, Kimura N, Jenko KJ, Kannan P, Hong J, Morse CL, Zoghbi SS, Gladding RL, Jacobson S, Oh U, Pike VW, Innis RB: Comparison of [(11)C](R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage 2010, 49: 2924–2932.PubMedCentralPubMedCrossRef
38.
Roivainen A, Någren K, Hirvonen J, Oikonen V, Virsu P, Tolvanen T, Rinne JO: Whole-body distribution and metabolism of [N-methyl-11C](R)-1-(2-chlorophenyl)-N(1-methylpropyl)-3-isoquinolinecarboxamide in humans; an imaging agent for in vivo assessment of peripheral benzodiazepine receptor activity with positron emission tomography. Eur J Nucl Med Mol Imaging 2009, 36: 671–682.PubMedCrossRef
39.
Ito H, Hietala J, Blomqvist G, Halldin C, Farde L: Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [11C]raclopride binding. J Cereb Blood Flow Metab 1998, 18: 941–950.PubMedCrossRef
40.
Olsson H, Halldin C, Swahn CG, Farde L: Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain. J Cereb Blood Flow Metab 1999, 19: 1164–1173.PubMedCrossRef
41.
James ML, Fulton RR, Henderson DJ, Eberl S, Meikle SR, Thomson S, Allan RD, Dolle F, Fulham MJ, Kassiou M: Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand. Bioorg Med Chem 2005, 13: 6188–6194.PubMedCrossRef
42.
Pardridge WM: Transport of protein-bound hormones into tissues in vivo. Endocrinol Rev 1982, 2: 103–123.CrossRef
43.
Lockhart A, Davis B, Matthews JC, Rahmoune H, Hong G, Gee A, Earnshaw D, Brown J: The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant alpha1-acid glycoprotein: implications for the use of the ligand as a CNS inflammatory marker. Nucl Med Biol 2003, 30: 199–206.PubMedCrossRef
44.
Fournier T, Medjoubi-N N, Porquet D: Alpha-1-acid glycoprotein. Biochim Biophys Acta 2000, 1482: 157–171.PubMedCrossRef
Metadata
Title
Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects
Authors
Aurelija Jučaite
Zsolt Cselényi
Annie Arvidsson
Gabrielle Åhlberg
Per Julin
Katarina Varnäs
Per Stenkrona
Jan Andersson
Christer Halldin
Lars Farde
Publication date
01-12-2012
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2012
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/2191-219X-2-15

Other articles of this Issue 1/2012

EJNMMI Research 1/2012 Go to the issue

Original research

Advanced brain dopamine transporter imaging in mice using small-animal SPECT/CT

Original research

A method for model-free partial volume correction in oncological PET

Original research

Comparative study of 64Cu/NOTA-[D-Tyr6,βAla11,Thi13,Nle14]BBN(6-14) monomer and dimers for prostate cancer PET imaging

Original research

A comparative 18F-FDG PET/CT imaging of experimental Staphylococcus aureus osteomyelitis and Staphylococcus epidermidis foreign-body-associated infection in the rabbit tibia

Original research

Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology

Original research

PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues