The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant α1-acid glycoprotein:: implications for the use of the ligand as a CNS inflammatory marker

被引:90
作者
Lockhart, A [1 ]
Davis, B
Matthews, JC
Rahmoune, H
Hong, GZ
Gee, A
Earnshaw, D
Brown, J
机构
[1] Addenbrookes Hosp, Addenbrookes Ctr Clin Invest, GlaxoSmithKline, Translat Med & Technol, Cambridge CB2 2GG, England
[2] GlaxoSmithKline, Harlow CM19 5AW, Essex, England
关键词
PK11195; PBR; alpha 1-acid glycoprotein; PET; orosomucoid;
D O I
10.1016/S0969-8051(02)00410-9
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
The peripheral benzodiazepine receptor ligand PK11195 has been used as an in vivo marker of neuroinflammation in positron emission tomography studies in man. One of the methodological issues surrounding the use of the ligand in these studies is the highly variable kinetic behavior of [C-11]PK11195 in plasma. We therefore undertook a study to measure the binding of [H-3]PK11195 to whole human blood and found a low level of binding to blood cells but extensive binding to plasma proteins. Binding assays using [H-3]PK11195 and purified human plasma proteins demonstrated a strong binding to alpha1-acid glycoprotein (AGP) and a much weaker interaction with albumin. Immunodepletion of AGP from plasma resulted in the loss of plasma [H-3]PK11195 binding demonstrating: (i) the specificity of the interaction and (ii) that AGP is the major plasma protein to which PK11195 binds with high affinity. PK11195 was able to displace fluorescein-dexamethasone from AGP with IC50 of < 1.2 mu M, consistent with a high affinity interaction. These findings are important for understanding the behavior of the ligand in positron emission tomography studies for three reasons. Firstly, AGP is an acute phase protein and its levels will vary during infection and pathological inflammatory diseases such as multiple sclerosis. This could significantly alter the free plasma concentrations of the ligand and contribute to its variable kinetic behavior. Secondly, AGP and AGP-bound ligand may contribute to the access of [C-11]PK11195 to the brain parenchyma in diseases with blood brain barrier breakdown. Finally, local synthesis of AGP at the site of brain injury may contribute the pattern of [C-11]PK11195 binding observed in neuroinflammatory diseases. (C) 2003 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:199 / 206
页数:8
相关论文
共 32 条
  • [1] Increased peripheral benzodiazepine binding sites and pentraxin 3 expression in the spinal cord during EAE: relation to inflammatory cytokines and modulation by dexamethasone and rolipram
    Agnello, D
    Carvelli, L
    Muzio, V
    Villa, P
    Bottazzi, B
    Polentarutti, N
    Mennini, T
    Mantovani, A
    Ghezzi, P
    [J]. JOURNAL OF NEUROIMMUNOLOGY, 2000, 109 (02) : 105 - 111
  • [2] STEREOSELECTIVE BINDING OF PROPRANOLOL ENANTIOMERS TO HUMAN ALPHA-1-ACID GLYCOPROTEIN AND HUMAN-PLASMA
    ALBANI, F
    RIVA, R
    CONTIN, M
    BARUZZI, A
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 18 (02) : 244 - 246
  • [3] FAMILY STUDY OF GENETIC AND ENVIRONMENTAL-FACTORS DETERMINING THE PROTEIN-BINDING OF PROPRANOLOL
    ALVAN, G
    BERGSTROM, K
    BORGA, O
    ISELIUS, L
    PEDERSEN, N
    [J]. EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1983, 25 (04) : 437 - 441
  • [4] [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis
    Banati, RB
    Goerres, GW
    Myers, R
    Gunn, RN
    Turkheimer, FE
    Kreutzberg, GW
    Brooks, DJ
    Jones, T
    Duncan, JS
    [J]. NEUROLOGY, 1999, 53 (09) : 2199 - 2203
  • [5] PK ('peripheral benzodiazepine') - Binding sites in the CNS indicate early and discrete brain lesions: Microautoradiographic detection of [H-3]PK11195 binding to activated microglia
    Banati, RB
    Myers, R
    Kreutzberg, GW
    [J]. JOURNAL OF NEUROCYTOLOGY, 1997, 26 (02): : 77 - 82
  • [6] The peripheral benzodiazepine binding site in the brain in multiple sclerosis -: Quantitative in vivo imaging of microglia as a measure of disease activity
    Banati, RB
    Newcombe, J
    Gunn, RN
    Cagnin, A
    Turkheimer, F
    Heppner, F
    Price, G
    Wegner, F
    Giovannoni, G
    Miller, DH
    Perkin, GD
    Smith, T
    Hewson, AK
    Bydder, G
    Kreutzberg, GW
    Jones, T
    Cuzner, ML
    Myers, R
    [J]. BRAIN, 2000, 123 : 2321 - 2337
  • [7] BERKOVICH A, 1993, LIFE SCI, V52, P1265, DOI 10.1016/0024-3205(93)90087-J
  • [8] Agrin and microvascular damage in Alzheimer's disease
    Berzin, TM
    Zipser, BD
    Rafii, MS
    Kuo-Leblanc, V
    Yancopoulos, GD
    Glass, DJ
    Fallon, JR
    Stopa, EG
    [J]. NEUROBIOLOGY OF AGING, 2000, 21 (02) : 349 - 355
  • [9] PRAZOSIN BINDING TO HUMAN ALPHA-1-ACID GLYCOPROTEIN (OROSOMUCOID), HUMAN-SERUM ALBUMIN, AND HUMAN-SERUM - FURTHER CHARACTERIZATION OF THE SINGLE DRUG-BINDING SITE OF OROSOMUCOID
    BRUNNER, F
    MULLER, WE
    [J]. JOURNAL OF PHARMACY AND PHARMACOLOGY, 1985, 37 (05) : 305 - 309
  • [10] In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion
    Cagnin, A
    Myers, R
    Gunn, RN
    Lawrence, AD
    Stevens, T
    Kreutzberg, GW
    Jones, T
    Banati, RB
    [J]. BRAIN, 2001, 124 : 2014 - 2027