Tritium-labeled (E,E)-2,5-bis(4′-hydroxy-3′-carboxystyryl)benzene as a probe for β-amyloid fibrils

Abstract

Accumulation of Aβ in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aβ production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aβ40 and Aβ42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research. Radiolabeled probes for the detection of amyloid plaques and fibrils in living subjects are important for noninvasive evaluation of AD diagnosis, progression, and differentiation of AD from other neurodegenerative diseases and age-related cognitive decline. Tritium-labeled (E,E)-1-[3H]-2,5-bis(4’-hydroxy-3’-carbomethoxystyryl)benzene possesses an improved level of chemical stability relative to a previously reported radioiodinated analog for radiometric quantification of Aβ plaque and tau pathology in brain tissue and in vitro studies with synthetic Aβ and tau fibrils.

Early striatal amyloid deposition distinguishes Down syndrome and autosomal dominant Alzheimer's disease from late‐onset amyloid deposition

“…This would suggest that there is an overall tracer by “cause” (ADAD or DS vs LOAD) binding pattern with contributions from both. In fact, Matveev et al, suggests that a distinct sub-fraction of Aβ is responsible for PiB binding, and in the case of DS and ADAD this sub-fraction may have a relatively higher volume in these sub-cortical regions (Matveev et al, 2014). These data suggest that at minimum the differences in tracers are likely an important contribution.…”

Down syndrome: age-dependence of PiB binding in postmortem frontal cortex across the lifespan

“…3 H-PiB binding was used to measure fibrillar Aβ and was assessed in homogenates of frontal cortex (Beckett, et al, 2012;Matveev, et al, 2014). Instead of the 10 μM concentrations typically used for histological assay, which will also bind to low affinity sites, we used 1.2 nM PiB, a concentration closer to the K d of the PiB analog CN-PiB for Aβ pathology and to the in vivo concentration of 11 C-PiB used to visualize high affinity PiB binding in human AD brain.…”

“…3 H-X-34 binding (Matveev, et al, 2014) was used to measure a combination of fibrillar Aβ and neurofibrillary tangles and was performed with 10 μl of a PBS homogenate containing 0.166 mg wet weight tissue similar to 3 H-PiB binding, with 5 nM 3 H-X-34, 23 Ci/mmol, custom titrated by Vitrax) (Matveev, et al, 2014) with 10 μM Congo Red as the nonradioactive X-34 competitor.…”

Amyloid fibril polymorphism: a challenge for molecular imaging and therapy

“…BS3 was least abundant and was associated with PIB binding. 3 H‐X34, a highly fluorescent analog of Congo red, binds to the BS2 Aβ site and is not effectively competed for by either ThT or PIB . ThT, Congo red and X34 seem to be pan‐amyloid specific, interacting with amyloid fibrils formed from a variety of proteins.…”