Binding of the positron emission tomography tracer Pittsburgh Compound-B reflects the amount of amyloid-β in Alzheimer's Disease brain but not in transgenic mouse brain

William E. Klunk, Brian J. Lopresti, Milos D. Ikonomovic, Iliya M. Lefterov, Radosveta P. Koldamova, Eric E. Abrahamson, Manik L. Debnath, Daniel P. Holt, Guo Feng Huang, Li Shao, Steven T. DeKosky, Julie C. Price, Chester A. Mathis

Research output: Contribution to journalArticlepeer-review

Abstract

During the development of in vivo amyloid imaging agents, an effort was made to use micro-positron emission tomography (PET) imaging in the presenilin-1 (PS1)/amyloid precursor protein (APP) transgenic mouse model of CNS amyloid deposition to screen new compounds and further study Pittsburgh Compound-B (PIB), a PET tracer that has been shown to be retained well in amyloid-containing areas of Alzheimer's disease (AD) brain. Unexpectedly, we saw no significant retention of PIB in this model even at 12 months of age when amyloid deposition in the PS1/APP mouse typically exceeds that seen in AD. This study describes a series of ex vivo and postmortem in vitro studies designed to explain this low retention. Ex vivo brain pharmacokinetic studies confirmed the low in vivo PIB retention observed in micro-PET experiments. In vitro binding studies showed that PS1/APP brain tissue contained less than one high-affinity (Kd = 1-2 nM) PIB binding site per 1000 molecules of amyloid-β (Aβ), whereas AD brain contained >500 PIB binding sites per 1000 molecules of Aβ. Synthetic Aβ closely resembled PS1/APP brain in having less than one high-affinity PIB binding site per 1000 molecules of Aβ, although the characteristics of the few high-affinity PIB binding sites found on synthetic Aβ were very similar to those found in AD brain. We hypothesize that differences in the time course of deposition or tissue factors present during deposition lead to differences in secondary structure between Aβ deposited in AD brain and either synthetic Aβ or Aβ deposited in PS1/APP brain.

Original languageEnglish (US)
Pages (from-to)10598-10606
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number46
DOIs
StatePublished - Nov 16 2005
Externally publishedYes

Keywords

  • Amyloid-β
  • Benzothiazole
  • Neuroimaging
  • Plaques
  • Positron emission tomography
  • Transgenic mouse

ASJC Scopus subject areas

  • Neuroscience(all)

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