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.
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.
Ramakrishnan
Muthu
M
Molecular Neurobiology Laboratory, Departments of Neurology and Neuroscience, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
Wengenack
Thomas M
TM
Kandimalla
Karunya K
KK
Curran
Geoffry L
GL
Gilles
Emily J
EJ
Ramirez-Alvarado
Marina
M
Lin
Joseph
J
Garwood
Michael
M
Jack
Clifford R
CR
Poduslo
Joseph F
JF
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
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