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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

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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.

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ACKNOWLEDGEMENTS

The authors would like to thank Dr. Karen Duff for the PS1 transgenic mouse line, Dawn Gregor for her expert technical assistance, and Dr. Thomas G. Beito and Dr. Chella S. David of the Mayo Monoclonal Core Facility. Thanks to Prof. Shawn Que Hee, director of ICP-MS facility for the ICP-mass spectral analysis. Support was provided by the Neuroscience Cores for MR Studies of the Brain from NINDS (NS057091) and the Minnesota Partnership for Biotechnology and Medical Genomics.

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Authors and Affiliations

  1. Molecular Neurobiology Laboratory, Departments of Neurology and Neuroscience, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota, 55905, USA

    Muthu Ramakrishnan, Thomas M. Wengenack, Karunya K. Kandimalla, Geoffry L. Curran, Emily J. Gilles & Joseph F. Poduslo

  2. College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida, USA

    Karunya K. Kandimalla

  3. Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Marina Ramirez-Alvarado

  4. Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota, Minneapolis, Minnesota, USA

    Joseph Lin & Michael Garwood

  5. Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Clifford R. Jack Jr.

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  1. Muthu Ramakrishnan
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  2. Thomas M. Wengenack
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  10. Joseph F. Poduslo
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Correspondence to Joseph F. Poduslo.

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Ramakrishnan, M., Wengenack, T.M., Kandimalla, K.K. et al. 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. Pharm Res 25, 1861–1872 (2008). https://doi.org/10.1007/s11095-008-9600-9

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  • DOI: https://doi.org/10.1007/s11095-008-9600-9

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