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

被引：168

作者：

Kroth, Heiko ^{[1
]}

Oden, Felix ^{[2
]}

Molette, Jerome ^{[1
]}

Schieferstein, Hanno ^{[3
,4
]}

Capotosti, Francesca ^{[1
]}

Mueller, Andre ^{[2
]}

Berndt, Mathias ^{[2
]}

Schmitt-Willich, Heribert ^{[2
]}

Darmency, Vincent ^{[1
]}

Gabellieri, Emanuele ^{[1
]}

Boudou, Cedric ^{[1
]}

Juergens, Tanja ^{[1
]}

Varisco, Yvan ^{[1
]}

Vokali, Efthymia ^{[1
]}

Hickman, David T. ^{[1
]}

Tamagnan, Gilles ^{[5
,6
]}

Pfeifer, Andrea ^{[1
]}

Dinkelborg, Ludger ^{[2
]}

Muhs, Andreas ^{[1
]}

Stephens, Andrew ^{[2
]}

机构：

[1] AC Immune SA, Lausanne, Switzerland

[2] Life Mol Imaging GmbH, Berlin, Germany

[3] Piramal Imaging GmbH, Berlin, Germany

[4] Merck KGaA, Darmstadt, Germany

[5] Invicro LLC, New Haven, CT USA

[6] XingImaging LLC, Beijing, Peoples R China

来源：

EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING | 2019年 / 46卷 / 10期

关键词：

Tau; PET; Positron-emission tomography; AD; Alzheimer's disease; Tauopathies; Fluorine-18; PET tracer; PI-2620; POSITRON-EMISSION-TOMOGRAPHY; NEUROFIBRILLARY TANGLES; MONOAMINE-OXIDASE; ISOFORMS; PROTEIN; DEGENERATION; STRATEGIES;

D O I：

10.1007/s00259-019-04397-2

中图分类号：

R8 [特种医学]; R445 [影像诊断学];

学科分类号：

1002 ; 100207 ; 1009 ;

摘要：

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 (A beta) 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 [F-18]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 A beta or MAO-A/B. Good brain uptake and fast washout were observed in healthy mice and non-human primates.ConclusionsTherefore, [F-18]PI-2620 was selected for clinical validation.

引用

页码：2178 / 2189

页数：12

共 40 条

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