title: Preclinical and first-in-man studies of [(11)C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography.
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-[(11)C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([(11)C]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 [(11)C]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 [(11)C]CB184, was evaluated. Acute toxicity of [(11)C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [(11)C]CB184 was also evaluated after the decay-out of (11)C. 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 [(11)C]CB184 in a normal human volunteer was performed.
  
  
  RESULTS
  A suitable preparation method for [(11)C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [(11)C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [(11)C]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 [(11)C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [(11)C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [(11)C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [(11)C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [(11)C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min.
  
  
  CONCLUSIONS
  [(11)C]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.
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan. toyohara@pet.tmig.or.jp.
authors.forename: Jun
authors.identifier: http://orcid.org/0000-0003-4721-405X
authors.initials: J
authors.lastname: Toyohara
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
authors.forename: Muneyuki
authors.initials: M
authors.lastname: Sakata
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hatano
authors.affiliation: Research Team for Aging Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yanai
authors.affiliation: Research Team for Aging Neuroscience, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Endo
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Wagatsuma
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishii
authors.affiliation: Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.|Institute of Cyclotron and Drug Discovery Research, Southern Tohoku Research Institute for Neuroscience, Koriyama, Japan.|Department of Biofunctional Imaging, Fukushima Medical University, Fukushima, Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Ishiwata
mesh_terms: D000328:Adult; D000818:Animals; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D011854:Radiochemistry; D011874:Radiometry; D051381:Rats; D018079:Receptors, GABA / Q000378:metabolism*; D014018:Tissue Distribution; D018675:Toxicity Tests
chemical_list: C000604727:CB184 compound; D002250:Carbon Radioisotopes; D007093:Imidazoles; D011725:Pyridines; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: Central nervous system; Positron emission tomography; TSPO; [11C]CB184