title: The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds to activated and infected brain macrophages in areas of synaptic degeneration: implications for PET imaging of neuroinflammation in lentiviral encephalitis.
abstract: HIV encephalitis (HIVE) is characterized by neurodegeneration mediated by toxins derived from infected and activated brain macrophages. Since the peripheral benzodiazepine receptor (PBR) is abundant on brain macrophages, we hypothesized that [(3)H]DAA1106, a new PBR ligand, can label infected and activated brain macrophages in HIVE. Using cell culture and postmortem brain tissues from HIVE and a macaque model of HIVE, we show that [(3)H]DAA1106 binds with high affinity to activated and infected macrophages in regions of synaptic damage. Further, binding affinity reflected by lower K(D) (dissociation constant) values and the B(max) (total number of binding sites) to K(D) ratios reflective of ligand-binding potential was significantly higher with [(3)H]DAA1106 compared to the extensively characterized PBR ligand [(3)H](R)-PK11195. These data suggest that DAA1106 binds with high affinity to activated and infected brain macrophages and possesses binding characteristics beneficial for in vivo use in the detection and clinical monitoring of HIVE using positron emission tomography.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.forename: Guoji
authors.initials: G
authors.lastname: Wang
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Wiley
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology* / Q000821:virology; D003994:Bucladesine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018792:Encephalitis, Viral / Q000473:pathology*; D005260:Female; D006801:Humans; D016086:Lentivirus; D008070:Lipopolysaccharides / Q000494:pharmacology; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010647:Phenyl Ethers / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000473:pathology*; D000097382:CD68 Molecule
chemical_list: D000081:Acetamides; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003994:Bucladesine; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D010647:Phenyl Ethers; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C118942:DAA 1106