Selective contrast enhancement of individual Alzheimer's disease amyloid plaques using a polyamine and Gd-DOTA conjugated antibody fragment against fibrillar Aβ42 for magnetic resonance molecular imaging

Muthu Ramakrishnan, Thomas M. Wengenack, Karunya K. Kandimalla, Geoffry L. Curran, Emily J. Gilles, Marina Ramirez-Alvarado, Joseph Lin, Michael Garwood, Clifford R. Jack, Joseph F. Poduslo

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Purpose. 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 Aβ42 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 Aβ40/42 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 T 1-weighted spin-echo images, which co-register with individual plaques observed on spatially matched T 2-weighted spin-echo image Conclusions. Development of such a molecular probe is expected to open new avenues for the diagnosis of AD.

Original languageEnglish (US)
Pages (from-to)1861-1872
Number of pages12
JournalPharmaceutical research
Volume25
Issue number8
DOIs
StatePublished - Aug 2008

Keywords

  • Alzheimer's disease
  • Amyloid plaques
  • Antibody fragments
  • Contrast agent
  • Magnetic resonance imaging

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