Pharmaceutical Research

, 25:1861

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

Authors

  • Muthu Ramakrishnan
    • Molecular Neurobiology Laboratory, Departments of Neurology and NeuroscienceMayo Clinic College of Medicine
  • Thomas M. Wengenack
    • Molecular Neurobiology Laboratory, Departments of Neurology and NeuroscienceMayo Clinic College of Medicine
  • Karunya K. Kandimalla
    • Molecular Neurobiology Laboratory, Departments of Neurology and NeuroscienceMayo Clinic College of Medicine
    • College of Pharmacy and Pharmaceutical SciencesFlorida A&M University
  • Geoffry L. Curran
    • Molecular Neurobiology Laboratory, Departments of Neurology and NeuroscienceMayo Clinic College of Medicine
  • Emily J. Gilles
    • Molecular Neurobiology Laboratory, Departments of Neurology and NeuroscienceMayo Clinic College of Medicine
  • Marina Ramirez-Alvarado
    • Department of Biochemistry and Molecular BiologyMayo Clinic College of Medicine
  • Joseph Lin
    • Center for Magnetic Resonance Research and Department of RadiologyUniversity of Minnesota
  • Michael Garwood
    • Center for Magnetic Resonance Research and Department of RadiologyUniversity of Minnesota
  • Clifford R. Jack Jr.
    • Department of RadiologyMayo Clinic College of Medicine
    • Molecular Neurobiology Laboratory, Departments of Neurology and NeuroscienceMayo Clinic College of Medicine
Research Paper

DOI: 10.1007/s11095-008-9600-9

Cite this article as:
Ramakrishnan, M., Wengenack, T.M., Kandimalla, K.K. et al. Pharm Res (2008) 25: 1861. doi:10.1007/s11095-008-9600-9

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 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.

KEY WORDS

Alzheimer’s diseaseamyloid plaquesantibody fragmentscontrast agentmagnetic resonance imaging

Copyright information

© Springer Science+Business Media, LLC 2008