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Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography

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Abstract

Objective

We performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[11C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([11C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions.

Methods

In vitro selectivity of CB184 was characterized. The radiation absorbed dose by [11C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is >10,000-fold higher than the clinical equivalent dose of [11C]CB184, was evaluated. Acute toxicity of [11C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [11C]CB184 was also evaluated after the decay-out of 11C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [11C]CB184 in a normal human volunteer was performed.

Results

A suitable preparation method for [11C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [11C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [11C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [11C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [11C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [11C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [11C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [11C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.

Conclusions

[11C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.

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References

  1. Venneti S, Lopresti B, Wiley CA. The peripheral benzodiazepine receptor in microglia: from pathology to imaging. Prog Neurobiol. 2006;80:308–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.

    Article  CAS  PubMed  Google Scholar 

  3. Graeber MB, Li W, Rodriguez ML. Role of microglia in CNS inflammation. FEBS Lett. 2011;585:3798–805.

    Article  CAS  PubMed  Google Scholar 

  4. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6:193–201.

    Article  PubMed  Google Scholar 

  5. Papadopoulos V, Baraldi M, Guilarte TR, Kundsen 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.

    Article  CAS  PubMed  Google Scholar 

  6. Banati RB. Visualizing microglia activation in vivo. Glia. 2002;40:206–17.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Diorio D, Welner SA, Butterworth RF, Meaney MJ, Suranyi-Cadotte BR. Peripheral benzodiazepine binding sites in Alzheimer’s disease frontal and temporal cortex. Neurobiol Aging. 1991;12:255–8.

    Article  CAS  PubMed  Google Scholar 

  10. Gulyas B, Makkai B, Kasa P, Gulya K, Bakota L, Varszegi S, et al. 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. Neurochem Int. 2009;54:28–36.

    Article  CAS  PubMed  Google Scholar 

  11. Venneti S, Wang G, Nguyen J, Wiley CA. The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders. J Neuropathol Exp Neurol. 2008;67:1001–10.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Sitte HH, Wanschitz J, Budka H, Berger ML. Autoradiography with [3H]PK11195 of spinal tract degeneration in amyotrophic lateral sclerosis. Acta Neuropathol. 2001;101:75–8.

    CAS  PubMed  Google Scholar 

  14. Doorduin J, de Vries EFJ, Dierckx RA, Klein HC. PET imaging of the peripheral benzodiazepine receptor: monitoring disease progression and therapy response in neurodegenerative disorders. Curr Pharm Des. 2008;14:3297–315.

    Article  CAS  PubMed  Google Scholar 

  15. Schweitzer PJ, Fallon BA, Mann JJ, Kumar JSD. PET tracers for the peripheral benzodiazepine receptor and uses thereof. Drug Discov Today. 2010;15:933–42.

    Article  CAS  PubMed  Google Scholar 

  16. Trapani A, Palazzo C, de Candia M, Lasora FM, Trapani G. Targeting of the translocator protein 18 kDa (TSPO): a valuable approach for nuclear and optical imaging of activated microglia. Bioconjug Chem. 2013;24:1415–28.

    Article  CAS  PubMed  Google Scholar 

  17. Owen DRJ, Matthews PM. Imaging brain microglial activation using positron emission tomography and translocator protein-specific radioligands. Int Rev Neurobiol. 2011;101:19–39.

    Article  CAS  PubMed  Google Scholar 

  18. Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H, et al. Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [11C]DAA1106. J Cereb Blood Flow Metab. 2007;27:173–84.

    Article  CAS  PubMed  Google Scholar 

  19. Fujimura Y, Zoghbi SS, Simeon FG, Taku A, Pike VW, Innis RB, et al. Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, 18F-PBR06. J Nucl Med. 2009;50:1047–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fujita M, Imaizumi M, Zoghbi SS, Fujimura Y, Farris AG, Suhara T, et al. Kinetic analysis in healthy human of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage. 2008;40:43–52.

    Article  PubMed  Google Scholar 

  21. Rusjan PM, Wilson AA, Bloomfield PM, Vitcu I, Meyer JH, Houle S, et al. Quantification of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab. 2011;31:1807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Endres CJ, Pomper MG, James M, Uzuner O, Hammoud DA, Watkins CC, et al. Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med. 2009;50:1276–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Arlicot N, Vercouillie J, Riberio MJ, Tauber C, Venel Y, Baulieu JL, et al. Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation. Nucl Med Biol. 2012;39:570–8.

    Article  CAS  PubMed  Google Scholar 

  24. Owen DRJ, Gunn RN, Rabiner EA, Bennacef I, Fujita M, Kreisl WC, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med. 2011;52:24–32.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang MR, 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.

    Article  CAS  PubMed  Google Scholar 

  26. Yanamoto K, Yamasaki T, Kumata K, Yui J, Odawara C, Kawamura K, et al. Evaluation of N-benzyl-N-[11C]methyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ([11C]DAC) as a novel translocator protein (18 kDa) radioligand in kainic acid-lesioned rat. Synapse. 2009;63:961–71.

    Article  CAS  PubMed  Google Scholar 

  27. Hatano K, Sekimata K, Yamada T, Abe J, Ito K, Ogawa M, et al. 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. Ann Nucl Med. 2015;29:325–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Garcia DV, de Vries EFJ, Toyohara J, Ishiwata K, Hatano K, Dierckx RAJO, et al. Evaluation of [11C]CB184 for imaging and quantification of TSPO overexpression in a rat model of herpes encephalitis. Eur J Nucl Med Mol Imaging. 2015;42:1106–18.

    Article  Google Scholar 

  29. Kirschner AS, Ice RD, Beierwaltes WH. Radiation dosimetry of 131I-19-iodocholesterol: the pitfalls of using tissue concentration data—reply. J Nucl Med. 1975;16:248–9.

    CAS  Google Scholar 

  30. Stabin MG, Sparks RB, Crowe E. OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 2005;46:1023–7.

    PubMed  Google Scholar 

  31. Yanai M, Semba M, Ito H, Endo S. Cilostazol improves hippocampus-dependent long-term memory in mice. Psychopharmacology. 2014;231:2681–93.

    Article  CAS  PubMed  Google Scholar 

  32. Watabe H, Channing MA, Der MG, Adams HR, Jagoda E, Herscovitch P, Eckelman WC, Carson RE. Kinetic analysis of the 5-HT2A ligand [11C]MDL100,907. J Cereb Blood Flow Metab. 2000;20:899–909.

    Article  CAS  PubMed  Google Scholar 

  33. Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab. 1990;19:615–23.

    Google Scholar 

  34. International Commission on Radiological Protection. 1990 recommendation of the International Commission on radiological protection: publication 60 Oxford. U.K.: Pergamon Press; 1990. p. 4–11.

    Google Scholar 

  35. van der Aart J, Hallett WA, Rabiner EA, Passhier J, Comley RA. Radiation dose estimates for carbon-11-labeled PET tracers. Nucl Med Biol. 2012;39:305–14.

    Article  PubMed  Google Scholar 

  36. Doble A, Malgorius C, Daniel M, Daniel N, Imbault F, Basbaum A, et al. Labelling of peripheral-type benzodiazepine binding sites in human brain with [3H]PK11195: anatomical and subcellular distribution. Brain Res Bull. 1987;18:49–61.

    Article  CAS  PubMed  Google Scholar 

  37. Su Z, Roncaroli F, Durrenberger PF, Coope DJ, Karabatsou K, Hinz R, et al. The 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology study. J Nucl Med. 2015;56:512–7.

    Article  CAS  PubMed  Google Scholar 

  38. Feng L, Svarer C, Thomsen G, de Nijs R, Larsen VA, Jensen P, et al. In vivo quantification of cerebral translocator protein binding in humans using 6-chloro-2-(4-[123I]iodophenyl)-3-(N, N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide SPECT. J Nucl Med. 2014;55:1966–72.

    Article  CAS  PubMed  Google Scholar 

  39. Kumar A, Muzik O, Shandal V, Chugani D, Chakraboty P, Chugani HT. Evaluation of age-related changes in translocator protein (TSPO) in human brain using 11C-[R]-PK1195 PET. J Neuroinflammation. 2012;9:232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Jučaite A, Cselényi Z, Arvidsson A, Åhlberg G, Julin P, Varnäs K, et al. Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain—a PET study in control subjects. EJNMMI Res. 2012;2:15.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Peyronneau MA, Saba W, Goutal S, Damont A, Dollé F, Kassiou M, et al. Metabolism and quantification of [18F]DPA-714, a new TSPO positron emission tomography radioligand. Drug Metab Dispos. 2013;41:122–31.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Mr. Kunpei Hayashi, Mr. Masanari Sakai, and Ms. Hatsumi Endo for technical assistance. This work was supported in part by the Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology, Japan (21-5), KAKENHI (24730642, 15H03103, 26115532, 25560382, 25293271). All authors disclose no potential conflicts of interest.

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Correspondence to Jun Toyohara.

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Toyohara, J., Sakata, M., Hatano, K. et al. Preclinical and first-in-man studies of [11C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography. Ann Nucl Med 30, 534–543 (2016). https://doi.org/10.1007/s12149-016-1094-7

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