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.
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页码:199 / 206
页数:8
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