Abstract
PurposeTau deposition is a key pathological feature of Alzheimer’s disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aβ) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies. Several PET tracers targeting tau deposits have been discovered and tested in humans. Limitations have been reported, especially regarding their selectivity.MethodsIn our screening campaign we identified pyrrolo[2,3-b:4,5-c’]dipyridine core structures with high affinity for aggregated tau. Further characterization showed that compounds containing this moiety had significantly reduced monoamine oxidase A (MAO-A) binding compared to pyrido[4,3-b]indole derivatives such as AV-1451.ResultsHere we present preclinical data of all ten fluoropyridine regioisomers attached to the pyrrolo[2,3-b:4,5-c’]dipyridine scaffold, revealing compounds 4 and 7 with superior properties. The lead candidate [18F]PI-2620 (compound 7) displayed high affinity for tau deposits in AD brain homogenate competition assays. Specific binding to pathological misfolded tau was further demonstrated by autoradiography on AD brain sections (Braak I-VI), Pick’s disease and progressive supranuclear palsy (PSP) pathology, whereas no specific tracer binding was detected on brain slices from non-demented donors. In addition to its high affinity binding to tau aggregates, the compound showed excellent selectivity with no off-target binding to Aβ or MAO-A/B. Good brain uptake and fast washout were observed in healthy mice and non-human primates.ConclusionsTherefore, [18F]PI-2620 was selected for clinical validation.
Highlights
Alzheimer’s disease (AD) is the most common age-related neurodegenerative condition [1, 2]
In order to improve the solubility of the nitroprecursors, Boc- or trityl protecting group was introduced at pyrrolo[2,3-b:4,5-c’]dipyridine NH-moiety, as both can be readily cleaved by acid at the end of synthesis
The Boc-protected precursor offered some advantages, such as better solubility compared to the described synthesis of [18F]3 using the corresponding unprotected precursor [12]
Summary
Alzheimer’s disease (AD) is the most common age-related neurodegenerative condition [1, 2]. The mechanisms of neurodegeneration in AD are not yet fully understood, the major pathological characteristics are plaques, composed of beta-amyloid (Aβ) peptides, and neurofibrillary tangles (NFTs), composed of hyperphosphorylated tubulin associated unit (tau) proteins. There are several validated positronemission tomography (PET) tracers available for the detection of Aβ aggregates in vivo that are recognized as important tools to support the diagnosis and clinical management of AD [3,4,5,6,7,8,9]. Aβ plaque formation occurs early in the disease. Aβ plaque load does not correlate well with cognitive performance, while tau tangles have been shown to have a close correlation to neurodegeneration and track better with cognitive decline. Detailed reviews of currently studied tracers can already be found in the literature [18,19,20]
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