Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-β ligand in transgenic mice

doi:10.1073/pnas.2034101100

Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-β ligand in transgenic mice

^*Department of Neurology/Alzheimer's Disease Research Laboratory, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129; and ^‡Departments of Psychiatry and Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom (received for review July 2, 2003)

Abstract

The lack of a specific biomarker makes preclinical diagnosis of Alzheimer's disease (AD) impossible, and it precludes assessment of therapies aimed at preventing or reversing the course of the disease. The development of a tool that enables direct, quantitative detection of the amyloid-β deposits found in the disease would provide an excellent biomarker. This article demonstrates the real-time biodistribution kinetics of an imaging agent in transgenic mouse models of AD. Using multiphoton microscopy, Pittsburgh compound B (PIB) was imaged with sub-μm resolution in the brains of living transgenic mice during peripheral administration. PIB entered the brain quickly and labeled amyloid deposits within minutes. The nonspecific binding was cleared rapidly, whereas specific labeling was prolonged. WT mice showed rapid brain entry and clearance of PIB without any binding. These results demonstrate that the compound PIB has the properties required for a good amyloid-imaging agent in humans with or at risk for AD.

Footnotes

↵ † To whom correspondence should be addressed. E-mail: bbacskai{at}partners.org.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: AD, Alzheimer's disease; PIB, Pittsburgh compound B; CAA, cerebral amyloid angiopathy; BBB, blood–brain barrier; PET, positron emission tomography; ROI, region of interest.