title: 11C-ER176, a Radioligand for 18-kDa Translocator Protein, Has Adequate Sensitivity to Robustly Image All Three Affinity Genotypes in Human Brain.
abstract: For PET imaging of 18-kDa translocator protein (TSPO), a biomarker of neuroinflammation, most second-generation radioligands are sensitive to the single nucleotide polymorphism rs6971; however, this is probably not the case for the prototypical agent11C-PK11195 (11C-labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide), which has a relatively lower signal-to-noise ratio. We recently found that11C-ER176 (11C-(R)-N-sec-butyl-4-(2-chlorophenyl)-N-methylquinazoline-2-carboxamide), a new analog of11C-(R)-PK11195, showed little sensitivity to rs6971 when tested in vitro and had high specific binding in monkey brain. This study sought, first, to determine whether the sensitivity of11C-ER176 in humans is similar to the low sensitivity measured in vitro and, second, to measure the nondisplaceable binding potential (BPND, or the ratio of specific-to-nondisplaceable uptake) of11C-ER176 in human brain.
  
  
  
  Nine healthy volunteers-3 high-affinity binders (HABs), 3 mixed-affinity binders (MABs), and 3 low-affinity binders (LABs)-were studied with whole-body11C-ER176 PET imaging. SUVs from 60 to 120 min after injection derived from each organ were compared between genotypes. Eight separate healthy volunteers-3 HABs, 3 MABs, and 2 LABs-underwent brain PET imaging. The 3 HABs underwent a repeated brain scan after TSPO blockade with XBD173 (N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenylpurin-9-yl)acetamide) to determine nondisplaceable distribution volume (VND) via Lassen occupancy plotting and thereby estimate BPNDin brain.
  
  
  
  Regional SUV averaged from 60 to 120 min after injection in brain and peripheral organs with high TSPO densities such as lung and spleen were greater in HABs than in LABs. On the basis of VNDdetermined via the occupancy plot, the whole-brain BPNDfor LABs was estimated to be 1.4 ± 0.8, which was much lower than that for HABs (4.2 ± 1.3) but about the same as that for HABs with11C-PBR28 ([methyl-11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine)) (∼1.2).
  
  
  
  Obvious in vivo sensitivity to rs6971 was observed in11C-ER176 that had not been expected from in vitro studies, suggesting that the future development of any improved radioligand for TSPO should consider the possibility that in vitro properties will not be reflected in vivo. We also found that11C-ER176 has adequately high BPNDfor all rs6971 genotypes. Thus, the new radioligand would likely have greater sensitivity in detecting abnormalities in patients.
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Talakad G
authors.initials: TG
authors.lastname: Lohith
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Stal
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Telu
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Sami S
authors.initials: SS
authors.lastname: Zoghbi
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Fisciano, Italy; and.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Castellano
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.affiliation: Department of Pharmacy, University of Pisa, Pisa, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Pike
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D003937:Diagnosis, Differential; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D015588:Observer Variation; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018079:Receptors, GABA / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: 11C-ER176; 18-kDa translocator protein (TSPO); XBD173; positron emission tomography; rs6971 polymorphism