title: A comparison of the high-affinity peripheral benzodiazepine receptor ligands DAA1106 and (R)-PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation.
abstract: Activated microglia are an important feature of many neurological diseases and can be imaged in vivo using 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a ligand that binds the peripheral benzodiazepine receptor (PBR). N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl) acetamide (DAA1106) is a new PBR-specific ligand that has been reported to bind to PBR with higher affinity compared with PK11195. We hypothesized that this high-affinity binding of DAA1106 to PBR will enable better delineation of microglia in vivo using positron emission tomography. [(3)H]DAA1106 showed higher binding affinity compared with [(3)H](R)-PK11195 in brain tissue derived from normal rats and the rats injected intrastriatally with 6-hydroxydopamine or lipopolysaccharide at the site of the lesion. Immunohistochemistry combined with autoradiography in brain tissues as well as correlation analyses showed that increased [(3)H]DAA1106 binding corresponded mainly to activated microglia. Finally, ex vivo autoradiography and positron emission tomography imaging in vivo showed greater retention of [(11)C]DAA1106 compared with [(11)C](R)-PK11195 in animals injected with either lipopolysaccaride or 6-hydroxydopamine at the site of lesion. These results indicate that DAA1106 binds with higher affinity to microglia in rat models of neuroinflammation when compared with PK11195, suggesting that [(11)C]DAA1106 may represent a significant improvement over [(11)C](R)-PK11195 for in vivo imaging of activated microglia in human neuroinflammatory disorders.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lopresti
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Guoji
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slagel
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: N Scott
authors.initials: NS
authors.lastname: Mason
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Chester A
authors.initials: CA
authors.lastname: Mathis
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Fischer
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Niccole J
authors.initials: NJ
authors.lastname: Larsen
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Mortimer
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Teresa G
authors.initials: TG
authors.lastname: Hastings
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zigmond
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USADepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USAMolecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Wiley
mesh_terms: D000081:Acetamides / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D005911:Gliosis / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D007546:Isoquinolines / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine; D010647:Phenyl Ethers / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
chemical_list: D000081:Acetamides; C118942:DAA 1106; D007546:Isoquinolines; D008024:Ligands; D008070:Lipopolysaccharides; D010647:Phenyl Ethers; D011963:Receptors, GABA-A; D014316:Tritium; D016627:Oxidopamine; C037850:PK 11195