Binding of the Positron Emission Tomography Tracer Pittsburgh Compound-B Reflects the Amount of Amyloid-{beta} in Alzheimer's Disease Brain But Not in Transgenic Mouse Brain

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 11/2005; 25(46):10598-606. DOI: 10.1523/JNEUROSCI.2990-05.2005
Source: PubMed


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 (K(d) = 1-2 nm) PIB binding site per 1000 molecules of amyloid-beta (Abeta), whereas AD brain contained >500 PIB binding sites per 1000 molecules of Abeta. Synthetic Abeta closely resembled PS1/APP brain in having less than one high-affinity PIB binding site per 1000 molecules of Abeta, although the characteristics of the few high-affinity PIB binding sites found on synthetic Abeta 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 Abeta deposited in AD brain and either synthetic Abeta or Abeta deposited in PS1/APP brain.

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    • "Several other amyloid tracers were developed: 2- (1-6-[(2-[F]Fluoroethyl)(methyl)amino]-2-naphthyl ethylidene)malononitrile ([ 18 F]FDDNP) [48], [ 11 C]AZD2184 [49], [ 11 C]SB-13 [50], [ 18 F]BAY94- 9172 [51], and [ 18 F]AmyvidTM [52]. Contrary, it was shown in APP transgenic mice that A plaques were only marginally captured by PET imaging [53] [54]. "
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    • "Molecular imaging procedures are suited to overcome the need for a neuropathologic examination to identify the underlying pathology of these diseases. The last two decades have been focused on developing novel Ab ligands for the noninvasive detection of Ab deposition in the brain [33] [53]. Among these tracers, 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}et- hylidene)malononitrile ( 18 F-FDDNP) was the only one reported to bind to not only Ab deposits but also NFTs [54]. "
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    • "The specific binding properties of [11C]PiB are still controversial, as is the correlation with the post-mortem histology of tissue taken from disease models established in animals (Klunk et al., 2005a; Toyama et al., 2005; Bacskai et al., 2007; Rosen et al., 2011). The tracer is known to pass the blood-brain barrier with comparative ease, which renders the uptake sensitive to blood flow differences, as well as amyloid load (Blomquist et al., 2008; Gjedde et al., 2013). "
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