Top

European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-04-2005 | Original Article

Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis

Authors: F. Mattner, A. Katsifis, M. Staykova, P. Ballantyne, D. O. Willenborg

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 5/2005

Abstract

Purpose

Peripheral benzodiazepine receptors (PBRs) are upregulated on macrophages and activated microglia, and radioligands for the PBRs can be used to detect in vivo neuroinflammatory changes in a variety of neurological insults, including multiple sclerosis. Substituted 2-phenyl imidazopyridine-3-acetamides with high affinity and selectivity for PBRs have been prepared that are suitable for radiolabelling with a number of positron emission tomography and single-photon emission computed tomography (SPECT) isotopes. In this investigation, the newly developed high-affinity PBR ligand 6-chloro-2-(4′-iodophenyl)-3-(N,N-diethyl)imidazo[1,2-a]pyridine-3-acetamide, or CLINDE, was radiolabelled with¹²³I and its biodistribution in the central nervous system (CNS) of rats with experimental autoimmune encephalomyelitis (EAE) evaluated.

Methods

EAE was induced in male Lewis rats by injection of an emulsion of myelin basic protein and incomplete Freund’s adjuvant containing Mycobacterium butyricum. Biodistribution studies with¹²³I-CLINDE were undertaken on EAE rats exhibiting different clinical disease severity and compared with results in controls. Disease severity was confirmed by histopathology in the spinal cord of rats. The relationship between inflammatory lesions and PBR ligand binding was investigated using ex vivo autoradiography and immunohistochemistry on rats with various clinical scores.

Results

¹²³I-CLINDE uptake was enhanced in the CNS of all rats exhibiting EAE when compared to controls. Binding reflected the ascending nature of EAE inflammation, with lumbar/sacral cord > thoracic cord > cervical cord > medulla. The amount of ligand binding also reflected the clinical severity of disease. Ex vivo autoradiography and immunohistochemistry revealed a good spatial correspondence between radioligand signal and foci of inflammation and in particular ED-1⁺ cells representing macrophages and microglia.

Conclusion

These results demonstrate the ability of ¹²³I-CLINDE to measure in vivo inflammatory events represented by increased density of PBRs and suggest that ¹²³I-CLINDE warrants further investigation as a potential SPECT marker for imaging of CNS inflammation.

Papadopoulos V, Amri H, Li H, Yao Z, Brown RC, Vidic B, et al. Structure, function and regulation of the mitochondrial peripheral-type benzodiazepine receptor. Therapie 2001;56:549–56.PubMed

Benavides J, Quarteronet D, Imbault F, Malgouris C, Uzan A, Renault C, et al. Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [³H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization. J Neurochem 1983; 41:1744–50.

Bono F, Lamarche I, Prabonnaud V, Le Fur G, Herbert JM. Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities. Biochem Biophys Res Commun 1999;265:457–61.CrossRefPubMed

Brown RC, Papadopoulos V. Role of the peripheral-type benzodiazepine receptor in adrenal and brain steroidogenesis. Int Rev Neurobiol 2001;46:117–43.CrossRefPubMed

Li H, Yao Z, Degenhardt B, Teper G, Papadopoulos V. Cholesterol binding at the cholesterol recognition/interaction amino acid consensus (CRAC) of the peripheral-type benzodiazepine receptor and inhibition of steroidogenesis by an HIV TAT-CRAC peptide. Proc Natl Acad Sci U S A 2001;98:1267–72.CrossRefPubMed

Culty M, Luo L, Yao ZX, Chen H, Papadopoulos V, Zirkin BR. Cholesterol transport, peripheral benzodiazepine receptor, and steroidogenesis in aging Leydig cells. J Androl 2002;23:439–47.PubMed

Banati RB. Visualising microglial activation in vivo. Glia 2002;40:206–17.CrossRefPubMed

Banati RB. Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. Br Med Bull 2003;65:121–31.CrossRefPubMed

Kuhlmann AC, Guilarte TR. Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity. J Neurochem 2000;74:1694–704.CrossRefPubMed

10.

Mankowski JL, Queen SE, Tarwater PJ, Adams RJ, Guilarte TR. Elevated peripheral benzodiazepine receptor expression in simian immunodeficiency virus encephalitis. J Neurovirol 2003;9:94–100.PubMed

11.

Messmer K, Reynolds GP. Increased peripheral benzodiazepine binding sites in the brain of patients with Huntington’s disease. Neurosci Lett 1998;241:53–6.CrossRefPubMed

12.

Cagnin A, Myers R, Gunn RN, Lawrence AD, Stevens T, Kreutzberg GW, et al. In vivo visualization of activated glia by [¹¹C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion. Brain 2001;124:2014–27.CrossRefPubMed

13.

Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, et al. The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000;123:2321–37.CrossRefPubMed

14.

Vowinckel E, Reutens D, Becher B, Verge G, Evans A, Owens T, et al. PK11195 binding to the peripheral benzodiazepine receptor as a marker of microglia activation in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neurosci Res 1997;50:345–53.PubMed

15.

Bruck W, Sommermeier N, Bergmann M, Zettl U, Goebel HH, Kretzschmar HA, et al. Macrophages in multiple sclerosis. Immunobiology 1996;195:588–600.PubMed

16.

Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–17.CrossRefPubMed

17.

Sobel RA. The pathology of multiple sclerosis. Neurol Clin 1995;13:1–21.PubMed

18.

Banati RB, Myers R, Kreutzberg GW. PK (‘peripheral benzodiazepine’)—binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [³H]PK11195 binding to activated microglia. J Neurocytol 1997;26:77–82.CrossRefPubMed

19.

Dumont F, De Vos F, Versijpt J, Jansen HM, Korf J, Dierckx RA, et al. In vivo evaluation in mice and metabolism in blood of human volunteers of [¹²³I]iodo-PK11195: a possible single-photon emission tomography tracer for visualization of inflammation. Eur J Nucl Med 1999;26:194–200.CrossRefPubMed

20.

Katsifis A, Mattner F, Mardon K, Papazian V, Dikic B. Synthesis and evaluation of [¹²³I]imidazo[1,2-a]pyridines as potential probes for the study of the peripheral benzodiazepine receptors using SPECT. J Nucl Med 1998;39(5):50.

21.

Katsifis A, Mattner F, Dikic B, Papazian V. Synthesis of substituted [¹²³I]imidazo[1,2-a]pyridines as potential probes for the study of the peripheral benzodiazepine receptors using SPECT. Radiochim Acta 2000;88(3–4):229–32.

22.

Eylar EH. The structure and immunologic properties of basic proteins of myelin. Ann N Y Acad Sci 1972;195:481–91.PubMed

23.

Mattner F, Papazian V, Chapman J, Katsifis A. Ex vivo pharmacological evaluation of the peripheral benzodiazepine receptor radioligand [¹²³I]-ClINDE in animal tumour models. J Lab Comp Radiopharm 2003;46:S9.

24.

Katsifis A, Mattner F, Chapman J, Izard B, Papazian V, Dikic B, et al. Synthesis and Evaluation of [¹²³I]-labelled peripheral benzodiazepine receptor ligands in tumour bearing rodents. Eur J Nucl Med Mol Imaging 2002;29:S163.CrossRef

25.

Debruyne JC, Versijpt J, Van Laere KJ, De Vos F, Keppens J, Strijckmans K, et al. PET visualization of microglia in multiple sclerosis patients using [¹¹C]PK11195. Eur J Neurol 2003;10:257–64.PubMed

Title: Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis
Authors: F. Mattner
A. Katsifis
M. Staykova
P. Ballantyne
D. O. Willenborg
Publication date: 01-04-2005
Publisher: Springer-Verlag
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 5/2005
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-004-1690-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Evaluation of a radiolabelled peripheral benzodiazepine receptor ligand in the central nervous system inflammation of experimental autoimmune encephalomyelitis: a possible probe for imaging multiple sclerosis

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 5/2005

Noninvasive radiological imaging of pulmonary gene transfer and expression using the human sodium iodide symporter

Sentinel lymph node detection following the hysteroscopic peritumoural injection of 99mTc-labelled albumin nanocolloid in endometrial cancer

Physiological 18F-FDG uptake in the ovaries and uterus of healthy female volunteers

Premature conclusions may harm good ideas

Role of 18F-FDG PET–CT imaging for the detection of an unknown primary tumour: preliminary results in 21 patients

Role of ultrasound in the detection of apoptosis