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Annals of Nuclear Medicine
Published in: Annals of Nuclear Medicine 4/2015

Open Access 01-05-2015 | Original Article

Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [11C]CB184 and [11C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [11C](R)-PK11195

Authors: Kentaro Hatano, Katsuhiko Sekimata, Takashi Yamada, Junichiro Abe, Kengo Ito, Mikako Ogawa, Yasuhiro Magata, Jun Toyohara, Kiichi Ishiwata, Giovanni Biggio, Mariangela Serra, Valentino Laquintana, Nunzio Denora, Andrea Latrofa, Giuseppe Trapani, Gaetano Liso, Hiromi Suzuki, Makoto Sawada, Masahiko Nomura, Hiroshi Toyama

Published in: Annals of Nuclear Medicine | Issue 4/2015

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Abstract

Objective

We report synthesis of two carbon-11 labeled imidazopyridines TSPO ligands, [11C]CB184 and [11C]CB190, for PET imaging of inflammatory process along with neurodegeneration, ischemia or brain tumor. Biodistribution of these compounds was compared with that of [11C]CB148 and [11C](R)-PK11195.

Methods

Both [11C]CB184 and [11C]CB190 having 11C-methoxyl group on an aromatic ring were readily prepared using [11C]methyl triflate. Biodistribution and metabolism of the compounds were examined with normal mice. An animal PET study using 6-hydroxydopamine treated rats as a model of neurodegeneration was pursued for proper estimation of feasibility of the radioligands to determine neuroinflammation process.

Results

[11C]CB184 and [11C]CB190 were obtained via O-methylation of corresponding desmethyl precursor using [11C]methyl triflate in radiochemical yield of 73 % (decay-corrected). In vivo validation as a TSPO radioligand was carried out using normal mice and lesioned rats. In mice, [11C]CB184 showed more uptake and specific binding than [11C]CB190. Metabolism studies showed that 36 % and 25 % of radioactivity in plasma remained unchanged 30 min after intravenous injection of [11C]CB184 and [11C]CB190, respectively. In the PET study using rats, lesioned side of the brain showed significantly higher uptake than contralateral side after i.v. injection of either [11C]CB184 or [11C](R)-PK11195. Indirect Logan plot analysis revealed distribution volume ratio (DVR) between the two sides which might indicate lesion-related elevation of TSPO binding. The DVR was 1.15 ± 0.10 for [11C](R)-PK11195 and was 1.15 ± 0.09 for [11C]CB184.

Conclusion

The sensitivity to detect neuroinflammation activity was similar for [11C]CB184 and [11C](R)-PK11195.
Literature
1.
Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, et al. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402–9.CrossRefPubMed
2.
Culty M, Li H, Boujrad N, Amri H, Vidic B, Bernassau JM, et al. In vitro studies on the role of the peripheral-type benzodiazepine receptor in steroidogenesis. J Steroid Biochem Mol Biol. 1999;69:123–30.CrossRefPubMed
3.
Szabo I, De Pinto V, Zoratti M. The mitochondrial permeability transition pore may comprise VDAC molecules. II. The electrophysiological properties of VDAC are compatible with those of the mitochondrial megachannel. FEBS Lett. 1993;330:206–10.CrossRefPubMed
4.
Golani I, Weizman A, Leschiner S, Spanier I, Eckstein N, Limor R, et al. Hormonal regulation of peripheral benzodiazepine receptor binding properties is mediated by subunit interaction. Biochemistry. 2001;40:10213–22.CrossRefPubMed
5.
Beurdeley-Thomas A, Miccoli L, Oudard S, Dutrillaux B, Poupon MF. The peripheral benzodiazepine receptors: a review. J Neuro Oncol. 2000;46:45–56.CrossRef
6.
Lacapere JJ, Papadopoulos V. Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis. Steroids. 2003;68:569–85.CrossRefPubMed
7.
8.
9.
Kreutzberg GW. Microglia; a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.CrossRefPubMed
10.
Ito F, Toyama H, Kudo G, Suzuki H, Hatano K, Ichise M, et al. Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [11C]PK11195 in rats. Ann Nucl Med. 2010;24:163–9.CrossRefPubMed
11.
Shah F, Hume S, Pike V, Ashworth S, McDermott J. Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviors as radioligands for PK binding sites in rats. Nucl Med Biol. 1994;21:573–81.CrossRefPubMed
12.
Belloli S, Moresco RM, Matarrese M, Biella G, Sanvito F, Simonelli P, et al. Evaluation of three quinoline carboxamide derivatives as potential radioligands for the in vivo PET imaging of neurodegeneration. Neurochem Int. 2004;44:433–40.CrossRefPubMed
13.
Petit-Taboué MC, Baron JC, Barré L, Travère JM, Speckel D, Camsonne R, et al. Brain kinetics and specific binding of [11C]PK 11195 to omega 3 sites in baboons: positron emission tomography study. Eur J Pharmacol. 1991;200:347–51.CrossRefPubMed
14.
Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BN, Luurtsema G, Windhorst AD, et al. Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J Cereb Blood Flow Metab. 2005;25:842–51.CrossRefPubMed
15.
Lockhart A, Davis B, Matthews JC, Rahmoune H, Hong G, Gee A, et al. 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.CrossRefPubMed
16.
Zhang M-R, Kida T, Noguchi J, Furutsuka K, Maeda J, Suhara T, et al. [11C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. Nucl Med Biol. 2003;30:513–9.CrossRefPubMed
17.
Zhang MR, Maeda J, Ogawa M, Noguchi J, Ito T, Yoshida Y, et al. Development of a new radioligand, N-(5-fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethoxyl-5-methoxy benzyl)acetamide, for PET imaging of peripheral benzodiazepine receptor in primate brain. J Med Chem. 2004;47:2228–35.CrossRefPubMed
18.
Briard E, Zoghbi S, Imaizumi M, Gourley J, Shetty U, Hong J, et al. Synthesis and evaluation of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo. J Med Chem. 2008;51:17–30.CrossRefPubMed
19.
Wilson A, Garcia A, Parkes H, McCormick P, Stephenson K, Houle S, et al. Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazipine receptors. Nucl Med Biol. 2008;35:305–14.CrossRefPubMed
20.
James M, Fulton R, Henderson D, Eberl S, Meikle S, Thomson S, et al. Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand. Bioorg Med Chem. 2005;13:6188–94.CrossRefPubMed
21.
Martín A, Boisgard R, Thézé B, Van Camp N, Kuhnast B, Damont A, et al. Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia. J Cereb Blood Flow Metab. 2010;30:230–41.CrossRefPubMedCentralPubMed
22.
Zhang M, Kumata K, Maeda J, Yanamoto K, Hatori A, Okada M, et al. 11C-AC-5216: a novel PET ligand for peripheral benzodiazepine receptors in the primate brain. J Nucl Med. 2007;48:1853–61.CrossRefPubMed
23.
Mattner F, Mardon K, Katsfis A. Pharmacological evaluation of [123I]-CLINDE: a radioiodinated imidazopyridine-3-acetamide for the study of peripheral benzodiazepine binding sites (PBBS). Eur J Nucl Med Mol Imaging. 2008;35:779–89.CrossRefPubMed
24.
Sekimata K, Hatano K, Ogawa M, Abe J, Magata Y, Biggio G, et al. Radiosynthesis and in vivo evaluation of N-[11C]methylated imidazopyridineacetamides as PET tracers for peripheral benzodiazepine receptors. Nucl Med Biol. 2008;35:327–34.CrossRefPubMed
25.
Denora N, Laquintana V, Pisu MG, Dore R, Murru L, Latrofa A, Trapani G, Sanna E. 2-Phenyl-imidazo[1,2-a]pyridine compounds containing hydrophilic groups as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity and electrophysiological studies. J Med Chem. 2008;2008(51):6876–87.CrossRef
26.
Toyama H, Hatano K, Suzuki H, Ichise M, Momosaki S, Kudo G, et al. In vivo imaging of microglial activation using a peripheral benzodiazepine receptor ligand: [11C]PK-11195 and animal PET following ethanol injury in rat striatum. Ann Nucl Med. 2008;22:417–24.CrossRefPubMed
27.
Bergeron M, Cadorette J, Beaudoin JF, Lepage MD, Robert G, Selivanov V, et al. Performance evaluation of the LabPET APD-based digital PET scanner. IEEE Trans Nulc Sci. 2009;56:10–6.CrossRef
28.
Converse AK, Larsen EC, Engle JW, Barnhart TE, Nickles RJ, Duncan ID. 11C-(R)-PK11195 PET imaging of microglial activation and response to minocycline in Zymosan-treated rats. J Nucl Med. 2011;52:257–62.CrossRefPubMedCentralPubMed
29.
Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16:834–40.CrossRefPubMed
30.
Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neurosci. 1990;39:151–70.CrossRef
31.
Chen MK, Baidoo K, Verina T, Guilarte TR. Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization. Brain. 2004;127:1379–92.CrossRefPubMed
32.
Boutin H, Chauveau F, Thominiaux C, Gregoire MC, James ML, Trebossen R, Hantraye P, Dolle F, Tavitian B, Kassiou M. 11C-DPA-713: a novel peripheral benzodiazepine receptor PET ligand for in vivo imaging of neuroinflammation. J Nucl Med. 2007;48:573–81.CrossRefPubMed
33.
Yasuno F, Kosaka J, Ota M, Higuchi M, Ito H, Fujimura Y, Nozaki S, Takahashi S, Mizukami K, Asada T, Suhara T. Increased binding of peripheral benzodiazepine receptor in mild cognitive impairment-dementia converters measured by positron emission tomography with [(11)C]DAA1106. Psychiatry Res. 2012;203:67–74.CrossRefPubMed
34.
Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, Hong J, Pike VW, Innis RB. Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage. 2008;40:43–52.CrossRefPubMedCentralPubMed
35.
Owen DR, Howell OW, Tang SP, Wells LA, Bennacef I, Bergstrom M, Gunn RN, Rabiner EA, Wilkins MR, Reynolds R, Matthews PM, Parker CA. Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab. 2010;30(9):1608–18.CrossRefPubMedCentralPubMed
Metadata
Title
Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [11C]CB184 and [11C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [11C](R)-PK11195
Authors
Kentaro Hatano
Katsuhiko Sekimata
Takashi Yamada
Junichiro Abe
Kengo Ito
Mikako Ogawa
Yasuhiro Magata
Jun Toyohara
Kiichi Ishiwata
Giovanni Biggio
Mariangela Serra
Valentino Laquintana
Nunzio Denora
Andrea Latrofa
Giuseppe Trapani
Gaetano Liso
Hiromi Suzuki
Makoto Sawada
Masahiko Nomura
Hiroshi Toyama
Publication date
01-05-2015
Publisher
Springer Japan
Published in
Annals of Nuclear Medicine / Issue 4/2015
Print ISSN: 0914-7187
Electronic ISSN: 1864-6433
DOI
https://doi.org/10.1007/s12149-015-0948-8

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