A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system

被引：63

作者：

Gulyas, Balazs ^{[1
]}

Makkai, Boglarka ^{[2
]}

Kasa, Peter ^{[3
]}

Gulya, Karoly ^{[4
,5
]}

Bakota, Lidia ^{[4
,5
]}

Varszegi, Szilvia ^{[4
,5
]}

Beliczai, Zsuzsa ^{[4
,5
]}

Andersson, Jan ^{[1
]}

Csiba, Laszlo ^{[2
]}

Thiele, Andrea ^{[6
]}

Dyrks, Thomas ^{[6
]}

Suhara, Tetsua ^{[7
]}

Suzuki, Kazutoshi ^{[7
]}

Higuchi, Makato ^{[7
]}

Halldin, Christer ^{[1
]}

机构：

[1] Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden

[2] Univ Debrecen, Med & Hlth Sci Ctr, Dept Neurol, H-4012 Debrecen, Hungary

[3] Univ Szeged, Dept Psychiat, H-6720 Szeged, Hungary

[4] Univ Szeged, Dept Cell Biol & Mol Med, Fac Med, H-6720 Szeged, Hungary

[5] Univ Szeged, Fac Sci & Informat, H-6720 Szeged, Hungary

[6] BayerScheringPharma AG, D-13353 Berlin, Germany

[7] Natl Inst Radiol Sci, Mol Imaging Ctr, Mol Neuroimaging Grp, Chiba 2638555, Japan

来源：

NEUROCHEMISTRY INTERNATIONAL | 2009年 / 54卷 / 01期

关键词：

Peripheral benzodiazepine receptor (PBR); TSPO (18 kDa translocator protein); DAA1106; I-125; PK11195; Vinpocetine; Human brain; Whole hemisphere autoradiography; Receptor binding; CENTRAL NERVOUS-SYSTEM; PROTEIN; 18; KDA; BINDING-SITES; IN-VIVO; MICROGLIAL ACTIVATION; MULTIPLE-SCLEROSIS; DIAZEPAM-H-3; BINDING; RAT-BRAIN; PET; LIGANDS;

D O I：

10.1016/j.neuint.2008.10.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The binding of two radiolabelled analogues (N-(5-[125I]Iodo-2-phenoxyphenyl)-N-(2,5-dimethoxybenzyl)acetamide ([125I]desfluoro-DAA1106) and N-(5-[125I]Fluoro-2-phenoxyphenyl)-N-(2-[125I]Iodo-5-methoxybenzyl)acetamide ([125I]desmethoxy-DAA1106) of the peripheral benzodiazepine receptor (PBR) (or TSPO, 18 kDa translocator protein) ligand DAA1106 was examined by in vitro autoradiography on human post mortem whole hemisphere brain slices obtained from Alzheimer's disease (AD) patients and age-matched controls. Both [I-125]desfluoro-IDAA1106 and [I-125]desmethoxy-IDAA1106 were effectively binding to various brain structures. The binding could be blocked by the unlabelled ligand as well as by other PBR specific ligands. With both radiolabelled compounds, the binding showed regional inhomogeneity and the specific binding values proved to be the highest in the hippocampus, temporal and parietal cortex, the basal ganglia and thalamus in the AD brains. Compared with age-matched control brains, specific binding in several brain structures (temporal and parietal lobes, thalamus and white matter) in Alzheimer brains was significantly higher, indicating that the radioligands can effectively label-activated microglia and the up-regulated PBR/TSPO system in AD. Complementary immunohistochemical studies demonstrated reactive microglia activation in the AD brain tissue and indicated that increased ligand binding coincides with increased regional microglia activation due to neuroinflammation. These investigations yield further support to the PBR/TSPO binding capacity of DAA1106 in human brain tissue, demonstrate the effective usefulness of its radioiodinated analogues as imaging biomarkers in post mortem human studies, and indicate that its radiolabelled analogues, labelled with short half-time bioisotopes, can serve as prospective in vivo imaging biomarkers of activated microglia and the up-regulated PBR/TSPO system in the human brain. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：28 / 36

页数：9

共 93 条

[21] Binding characteristics of [3H]DAA1106, a novel and selective ligand for peripheral benzodiazepine receptors [J].

Chaki, S ;

Funakoshi, T ;

Yoshikawa, R ;

Okuyama, S ;

Okubo, T ;

Nakazato, A ;

Nagamine, M ;

Tomisawa, K .

EUROPEAN JOURNAL OF PHARMACOLOGY, 1999, 371 (2-3) :197-204

[22]

Chen CW, 2008, IEEE T CIRC SYST VID, V18, P1, DOI 10.1109/TCSVT.2008.915632

[23] Peripheral benzodiazepine receptor binding properties and effects on steroid synthesis of two new phenoxyphenyl-acetamide derivatives, DAA1097 and DAA1106 [J].

Culty, M ;

Silver, P ;

Nakazato, A ;

Gazouli, M ;

Li, H ;

Muramatsu, M ;

Okuyama, S ;

Papadopoulos, V .

DRUG DEVELOPMENT RESEARCH, 2001, 52 (03) :475-484

[24] EVIDENCE FOR SPECIES-DIFFERENCES IN PERIPHERAL BENZODIAZEPINE RECEPTORS - AN AUTORADIOGRAPHIC STUDY [J].

CYMERMAN, U ;

PAZOS, A ;

PALACIOS, JM .

NEUROSCIENCE LETTERS, 1986, 66 (02) :153-158

[25] PET visualization of microglia in multiple sclerosis patients using [11C]PK11195 [J].

Debruyne, JC ;

Versijpt, J ;

Van Laere, KJ ;

De Vos, F ;

Keppens, J ;

Strijckmans, K ;

Achten, E ;

Slegers, G ;

Dierckx, RA ;

Korf, J ;

De Reuck, JL .

EUROPEAN JOURNAL OF NEUROLOGY, 2003, 10 (03) :257-264

[26] PERIPHERAL BENZODIAZEPINE BINDING-SITES IN ALZHEIMERS-DISEASE FRONTAL AND TEMPORAL CORTEX [J].

DIORIO, D ;

WELNER, SA ;

BUTTERWORTH, RF ;

MEANEY, MJ ;

SURANYICADOTTE, BE .

NEUROBIOLOGY OF AGING, 1991, 12 (03) :255-258

[27] Peripheral benzodiazepine receptors: Molecular pharmacology to possible physiological significance in stress-induced hypertension [J].

Drugan, RC .

CLINICAL NEUROPHARMACOLOGY, 1996, 19 (06) :475-496

[28]

GALLAGER DW, 1981, J NEUROSCI, V1, P218

[29] BIOCHEMICAL, PHYSIOLOGICAL, AND PATHOLOGICAL ASPECTS OF THE PERIPHERAL BENZODIAZEPINE RECEPTOR [J].

GAVISH, M ;

KATZ, Y ;

BARAMI, S ;

WEIZMAN, R .

JOURNAL OF NEUROCHEMISTRY, 1992, 58 (05) :1589-1601

[30]

GROOM GN, 1995, J NUCL MED, V36, P2207

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