Discovery and preclinical characterization of [18F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer’s disease and other tauopathies

Abstract

Purpose Tau 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. Methods In 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. Results Here 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 [ 18 F]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. Conclusions Therefore, [ 18 F]PI-2620 was selected for clinical validation. Electronic supplementary material The online version of this article (10.1007/s00259-019-04397-2) contains supplementary material, which is available to authorized users.

PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape

“…In autoradiography studies it also showed to tau aggregates/folds in PSP brain sections, which of course has been controversial, since many tau tracers has been reported not to be bind to tau deposits in PSP in autoradiography experiments. However, off-target binding was observed in the pars compacta portion of the substantia nigra in human brain sections, consistent with the affinity of some tau tracers like flortaucipir, [ 18 F]MK-6240 to melanin-containing cells [52,53,201].…”

Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment

“…One AD subject who was in a very mild stage of the disease demonstrated no uptake. faced by tau tracers from prior generations, was also demonstrated (Kroth et al, 2019;Stephens et al, 2018 ommended for further investigation as minimal binding was found in controls and patients with AD had region-specific patterns of tracer uptake consistent with pathohistological data for the spread of tau pathology (Wong et al, 2018). Not only does [ 18 F]GTP1 retention correspond to established patterns of brain tau distribution in AD, but this new second-generation tau tracer was also correlated with performance on cognitive measures, particularly in the earliest stages of AD (Bohórquez et al, 2019;Teng et al, 2018;Teng et al, 2019).…”

“…In two AD subjects in advanced disease stages, uptake was also found in neocortical temporal, frontal, and parietal areas. Kroth et al (2019) [ 18 F]PI-2620 Four AD patients, two healthy controls Three AD subjects showed asymmetric distributions of tracer retention in temporal regions, the precuneus, and post-cingulate. One AD subject who was in a very mild stage of the disease demonstrated no uptake.…”

Detection of cerebral tauopathy in P301L mice using high-resolution large-field multifocal illumination fluorescence microscopy

“…This designates tauopathy an important target for early diagnostic and therapeutic intervention for Alzheimer's disease, FTLD, and other tauopathy disorders [6]. Tau tracers for positron emission tomography (PET) have been developed recently [5,[7][8][9][10][11][12], while tau imaging has emerged as a useful tool for disease staging, progression prediction, treatment stratification, and monitoring in clinical research setting.…”

“…Whole brain highresolution tau imaging in these disease models provide insights for mechanistic and therapeutic studies [18,19]. At macroscopic level, in vivo imaging of tauopathy was enabled by PET in P301L mouse line using 11 C-PBB3 [20][21][22] or 18 F-PI-2620 [10] tau probes. However, the limited resolution of microPET (1 mm) relative to the mouse brain (~10 mm 3 ) and the need for dedicated and expensive infrastructure for radiolabeling limit usability in preclinical setting.…”