title: Selective contrast enhancement of individual Alzheimer's disease amyloid plaques using a polyamine and Gd-DOTA conjugated antibody fragment against fibrillar Abeta42 for magnetic resonance molecular imaging.
abstract: OBJECTIVE
  The lack of an in vivo diagnostic test for AD has prompted the targeting of amyloid plaques with diagnostic imaging probes. We describe the development of a contrast agent (CA) for magnetic resonance microimaging that utilizes the F(ab')2 fragment of a monoclonal antibody raised against fibrillar human Abeta42
  
  
  METHODS
  This fragment is polyamine modified to enhance its BBB permeability and its ability to bind to amyloid plaques. It is also conjugated with a chelator and gadolinium for subsequent imaging of individual amyloid plaques
  
  
  RESULTS
  Pharmacokinetic studies demonstrated this 125I-CA has higher BBB permeability and lower accumulation in the liver and kidney than F(ab')2 in WT mice. The CA retains its ability to bind Abeta40/42 monomers/fibrils and also binds to amyloid plaques in sections of AD mouse brain. Intravenous injection of 125I-CA into the AD mouse demonstrates targeting of amyloid plaques throughout the cortex/hippocampus as detected by emulsion autoradiography. Incubation of AD mouse brain slices in vitro with this CA resulted in selective enhancement on T1-weighted spin-echo images, which co-register with individual plaques observed on spatially matched T2-weighted spin-echo image
  
  
  CONCLUSIONS
  Development of such a molecular probe is expected to open new avenues for the diagnosis of AD.
authors.affiliation: Molecular Neurobiology Laboratory, Departments of Neurology and Neuroscience, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
authors.forename: Muthu
authors.initials: M
authors.lastname: Ramakrishnan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wengenack
authors.forename: Karunya K
authors.initials: KK
authors.lastname: Kandimalla
authors.forename: Geoffry L
authors.initials: GL
authors.lastname: Curran
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Gilles
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
authors.forename: Joseph
authors.initials: J
authors.lastname: Lin
authors.forename: Michael
authors.initials: M
authors.lastname: Garwood
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D002854:Chromatography, Paper; D003287:Contrast Media / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000276:immunology*; D058225:Plaque, Amyloid / Q000473:pathology*; D011073:Polyamines
chemical_list: D016229:Amyloid beta-Peptides; D003287:Contrast Media; D006571:Heterocyclic Compounds; D007140:Immunoglobulin Fab Fragments; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D009942:Organometallic Compounds; D010446:Peptide Fragments; D011073:Polyamines; C075222:amyloid beta-protein (1-42); C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate