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The Journal of Neuroscience, 2001, 21:RC189:1-5

RAPID COMMUNICATION
Binding Characteristics of Radiofluorinated 6-Dialkylamino-2-Naphthylethylidene Derivatives as Positron Emission Tomography Imaging Probes for -Amyloid Plaques in Alzheimer's Disease

Eric D. Agdeppa¹, Vladimir Kepe¹, Jie Liu¹, Samuel Flores-Torres³, Nagichettiar Satyamurthy¹, Andrej Petric⁴, Greg M. Cole⁵, Gary W. Small², Sung-Cheng Huang¹, and Jorge R. Barrio¹

¹ Division of Nuclear Medicine, Department of Molecular and Medical Pharmacology, Laboratory of Structural Biology and Molecular Medicine, and ² Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles School of Medicine, Los Angeles, California 90095, ³ University of Puerto Rico, Cayey, Puerto Rico 00736, ⁴ Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia, and ⁵ Veterans Administration Hospital, Sepulveda, California 91343

Senile plaques (SPs) and neurofibrillary tangles (NFTs) are hallmark pathologies accompanying the neurodegeneration involved in Alzheimer's disease (AD), for which -amyloid (A) peptide is a major constituent of SPs. Our laboratories previously developed the hydrophobic, fluorescent molecular-imaging probe 2-(1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([¹⁸F]FDDNP), which crosses the blood-brain barrier and determines the localization and load of SPs and NFTs in vivo in AD patients. In this report, we used fluorimetric and radioactive binding assays to determine the binding affinities of FDDNP and its analog, 1-{6-[(2-[¹⁸F]fluoroethyl)(methyl)amino]naphthalen-2-yl}ethanone ([¹⁸F]FENE), to synthetic fibrils of A(1-40). FDDNP and FENE both appeared to bind to two kinetically distinguishable binding sites on A(1-40) fibrils. Fluorescence titrations yielded apparent K_d values of 0.12 and 0.16 nM for high-affinity binding sites for FDDNP and FENE, respectively, and apparent K_d values of 1.86 and 71.2 nM for the low-affinity binding sites. The traditional radioactive binding assays also produced apparent K_d values in the low nanomolar range. The presence of two kinetically distinguishable binding sites for FDDNP and FENE suggests multiple binding sites for SPs and identifies the parameters that allow for the structural optimization of this family of probes for in vivo use. The high-affinity binding of the probes to multiple binding sites on fibrils are consistent with results obtained with digital autoradiography, immunohistochemistry, and confocal fluorescence microscopy using human brain specimens of AD patients.

Key words: -amyloid fibrils; molecular-imaging probes; Alzheimer's disease; fluorescence titration; confocal fluorescence microscopy; digital autoradiography

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Copyright © Society for Neuroscience  0270-6474//$05.00/0

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