title: Design and chemical synthesis of a magnetic resonance contrast agent with enhanced in vitro binding, high blood-brain barrier permeability, and in vivo targeting to Alzheimer's disease amyloid plaques.
abstract: Molecular imaging is an important new direction in medical diagnosis; however, its success is dependent upon molecular probes that demonstrate selective tissue targeting. We report the design and chemical synthesis of a derivative of human amyloid-beta (Abeta) peptide that is capable of selectively targeting individual amyloid plaques in the brain of Alzheimer's disease transgenic mice after being intravenously injected. This derivative is based on the sequence of the first 30 amino acid residues of Abeta with asparagyl/glutamyl-4-aminobutane residues (N-4ab/Q-4ab) substituted at unique Asp and Glu positions and with Gd-DTPA-aminohexanoic acid covalently attached at the N-terminal Asp. The Gd[N-4ab/Q-4ab]Abeta30 peptide was homogeneous as shown by high-resolution analytical techniques with a mass of +/-4385 Da determined by electrospray ionization mass spectrometry. This diamine- and gadolinium-substituted derivative of Abeta is shown to have enhanced in vitro binding to Alzheimer's disease (AD) amyloid plaques and increased in vivo permeability at the blood-brain barrier because of the unique Asp/Glu substitutions. In addition, specific in vivo targeting to AD amyloid plaques is demonstrated throughout the brain of an APP, PS1 transgenic mouse after intravenous injection. Because of the magnetic resonance (MR) imaging contrast enhancement provided by gadolinium, this derivative should enable the in vivo MR imaging of individual amyloid plaques in the brains of AD animals or patients to allow for early diagnosis and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed.
authors.affiliation: Molecular Neurobiology Laboratory, Department of Neurology, Mayo Clinic School of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Poduslo
authors.forename: Geoffry L
authors.initials: GL
authors.lastname: Curran
authors.forename: Jane A
authors.initials: JA
authors.lastname: Peterson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McCormick
authors.forename: Abdul H
authors.initials: AH
authors.lastname: Fauq
authors.forename: Murad A
authors.initials: MA
authors.lastname: Khan
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wengenack
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002208:Caproates / Q000737:chemistry; D003287:Contrast Media / Q000378:metabolism*; D015195:Drug Design; D019786:Gadolinium DTPA / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*; D053764:Presenilin-1; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D016229:Amyloid beta-Peptides; D002208:Caproates; D003287:Contrast Media; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C037652:hexanoic acid; D019786:Gadolinium DTPA