schliessen

Filtern

 

Bibliotheken

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

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 prove... Full description

Journal Title: European Journal of Nuclear Medicine and Molecular Imaging 2019-07-01, Vol.46 (10), p.2178-2189
Main Author: Kroth, Heiko
Other Authors: Oden, Felix , Molette, Jerome , Schieferstein, Hanno , Capotosti, Francesca , Mueller, Andre , Berndt, Mathias , Schmitt-Willich, Heribert , Darmency, Vincent , Gabellieri, Emanuele , Boudou, Cédric , Juergens, Tanja , Varisco, Yvan , Vokali, Efthymia , Hickman, David T , Tamagnan, Gilles , Pfeifer, Andrea , Dinkelborg, Ludger , Muhs, Andreas , Stephens, Andrew
Format: Electronic Article Electronic Article
Language: English
Subjects:
PET
Tau
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
ID: ISSN: 1619-7070
Link: https://www.ncbi.nlm.nih.gov/pubmed/31264169
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6667408
title: 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
format: Article
creator:
  • Kroth, Heiko
  • Oden, Felix
  • Molette, Jerome
  • Schieferstein, Hanno
  • Capotosti, Francesca
  • Mueller, Andre
  • Berndt, Mathias
  • Schmitt-Willich, Heribert
  • Darmency, Vincent
  • Gabellieri, Emanuele
  • Boudou, Cédric
  • Juergens, Tanja
  • Varisco, Yvan
  • Vokali, Efthymia
  • Hickman, David T
  • Tamagnan, Gilles
  • Pfeifer, Andrea
  • Dinkelborg, Ludger
  • Muhs, Andreas
  • Stephens, Andrew
subjects:
  • Affinity
  • Aggregates
  • Alzheimer's disease
  • Amine oxidase (flavin-containing)
  • Autoradiography
  • Binding
  • Brain
  • Brain slice preparation
  • Cardiology
  • Cognitive ability
  • emission tomography
  • Fluorine
  • Fluorine-18
  • Imaging
  • Indoles
  • Medicine
  • Medicine & Public Health
  • Neurodegenerative diseases
  • Neurofibrillary tangles
  • Nuclear Medicine
  • Oncology
  • Original
  • Original Article
  • Orthopedics
  • Paralysis
  • Pathology
  • PET
  • PET tracer
  • PI-2620
  • Positron
  • Positron emission
  • Positron emission tomography
  • Primates
  • Progressive supranuclear palsy
  • Radiology
  • Selectivity
  • Tau
  • Tau protein
  • Tauopathies
  • Tomography
  • Tracers
  • Translational research
ispartof: European Journal of Nuclear Medicine and Molecular Imaging, 2019-07-01, Vol.46 (10), p.2178-2189
description: 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.
language: eng
source:
identifier: ISSN: 1619-7070
fulltext: no_fulltext
issn:
  • 1619-7070
  • 1619-7089
url: Link


@attributes
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
RANK2.754346
LOCALfalse
PrimoNMBib
record
control
sourceidproquest_pubme
recordidTN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6667408
sourceformatXML
sourcesystemPC
sourcerecordid2250343103
originalsourceidFETCH-LOGICAL-1495t-edbe6cd0b981b3b13d517b52449d487698c2f15d5e141f5753a9a5512babdd9a0
addsrcrecordideNp9ks1u1DAUhSMEoqXwAiyQJTZdEPBvEm-QqtLSSpXooqwQshz7esZVxh7sTMV0xWvwFLwTT4LTlEJZsLBs637n-Or6VNVzgl8TjNs3GWMqZI1JWZzJtqYPql3SlGuLO_nw7tzinepJzpcYk4528nG1wwhtOGnkbvXjnc8mXkHaIh0sWicwgw_e6AGZpU7ajJD8tR59DCg69Il0x5_PT2vaUPwKaRTg61gvIECakVFv0PnRBRqLEhJyMaFxCUjnDDmvIIyTyQSt9biMQ1xskQ_oYLhegl9B-vnte0bWZ9AZbvqJRZ0mQZwEHvLT6pHTQ4Znt_te9fH46OLwpD778P708OCsJlyKsQbbQ2Ms7mVHetYTZgVpe0E5l5Z3bSM7Qx0RVgDhxIlWMC21EIT2urdWarxXvZ1915t-BdaU1pMe1Dr5lU5bFbVX9yvBL9UiXqmmaVqOu2JwMhvENQTtE9zT2gCjilbRplWcY250K1zXcGOEYc643knmnBFAO1us9m97SfHLBvKoVuXTYBh0gLjJilJBCGZtxwr68h_0Mm5SKJOaKMw4K2Ch6EyZFHNO4O56I1hN0VJztFSJlrqJlqJF9OLvidxJfmepAGwGcimFBaQ_b__H9hcB99zp
sourcetypeOpen Access Repository
isCDItrue
recordtypearticle
pqid2250343103
display
typearticle
titleDiscovery 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
creatorKroth, Heiko ; Oden, Felix ; Molette, Jerome ; Schieferstein, Hanno ; Capotosti, Francesca ; Mueller, Andre ; Berndt, Mathias ; Schmitt-Willich, Heribert ; Darmency, Vincent ; Gabellieri, Emanuele ; Boudou, Cédric ; Juergens, Tanja ; Varisco, Yvan ; Vokali, Efthymia ; Hickman, David T ; Tamagnan, Gilles ; Pfeifer, Andrea ; Dinkelborg, Ludger ; Muhs, Andreas ; Stephens, Andrew
creatorcontribKroth, Heiko ; Oden, Felix ; Molette, Jerome ; Schieferstein, Hanno ; Capotosti, Francesca ; Mueller, Andre ; Berndt, Mathias ; Schmitt-Willich, Heribert ; Darmency, Vincent ; Gabellieri, Emanuele ; Boudou, Cédric ; Juergens, Tanja ; Varisco, Yvan ; Vokali, Efthymia ; Hickman, David T ; Tamagnan, Gilles ; Pfeifer, Andrea ; Dinkelborg, Ludger ; Muhs, Andreas ; Stephens, Andrew
descriptionPurpose 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.
identifier
0ISSN: 1619-7070
1EISSN: 1619-7089
2DOI: 10.1007/s00259-019-04397-2
3PMID: 31264169
languageeng
publisherBerlin/Heidelberg: Springer Berlin Heidelberg
subjectAffinity ; Aggregates ; Alzheimer's disease ; Amine oxidase (flavin-containing) ; Autoradiography ; Binding ; Brain ; Brain slice preparation ; Cardiology ; Cognitive ability ; emission tomography ; Fluorine ; Fluorine-18 ; Imaging ; Indoles ; Medicine ; Medicine & Public Health ; Neurodegenerative diseases ; Neurofibrillary tangles ; Nuclear Medicine ; Oncology ; Original ; Original Article ; Orthopedics ; Paralysis ; Pathology ; PET ; PET tracer ; PI-2620 ; Positron ; Positron emission ; Positron emission tomography ; Primates ; Progressive supranuclear palsy ; Radiology ; Selectivity ; Tau ; Tau protein ; Tauopathies ; Tomography ; Tracers ; Translational research
ispartofEuropean Journal of Nuclear Medicine and Molecular Imaging, 2019-07-01, Vol.46 (10), p.2178-2189
rights
0The Author(s) 2019
1European Journal of Nuclear Medicine and Molecular Imaging is a copyright of Springer, (2019). All Rights Reserved. © 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
lds50peer_reviewed
oafree_for_read
citesFETCH-LOGICAL-1495t-edbe6cd0b981b3b13d517b52449d487698c2f15d5e141f5753a9a5512babdd9a0
orcidid0000-0001-5052-6586
links
openurl$$Topenurl_article
thumbnail$$Usyndetics_thumb_exl
backlink$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31264169$$D View this record in MEDLINE/PubMed
search
creatorcontrib
0Kroth, Heiko
1Oden, Felix
2Molette, Jerome
3Schieferstein, Hanno
4Capotosti, Francesca
5Mueller, Andre
6Berndt, Mathias
7Schmitt-Willich, Heribert
8Darmency, Vincent
9Gabellieri, Emanuele
10Boudou, Cédric
11Juergens, Tanja
12Varisco, Yvan
13Vokali, Efthymia
14Hickman, David T
15Tamagnan, Gilles
16Pfeifer, Andrea
17Dinkelborg, Ludger
18Muhs, Andreas
19Stephens, Andrew
title
0Discovery 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
1European Journal of Nuclear Medicine and Molecular Imaging
addtitle
0Eur J Nucl Med Mol Imaging
1Eur J Nucl Med Mol Imaging
descriptionPurpose 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.
subject
0Affinity
1Aggregates
2Alzheimer's disease
3Amine oxidase (flavin-containing)
4Autoradiography
5Binding
6Brain
7Brain slice preparation
8Cardiology
9Cognitive ability
10emission tomography
11Fluorine
12Fluorine-18
13Imaging
14Indoles
15Medicine
16Medicine & Public Health
17Neurodegenerative diseases
18Neurofibrillary tangles
19Nuclear Medicine
20Oncology
21Original
22Original Article
23Orthopedics
24Paralysis
25Pathology
26PET
27PET tracer
28PI-2620
29Positron
30Positron emission
31Positron emission tomography
32Primates
33Progressive supranuclear palsy
34Radiology
35Selectivity
36Tau
37Tau protein
38Tauopathies
39Tomography
40Tracers
41Translational research
issn
01619-7070
11619-7089
fulltextfalse
rsrctypearticle
creationdate2019
recordtypearticle
recordideNp9ks1u1DAUhSMEoqXwAiyQJTZdEPBvEm-QqtLSSpXooqwQshz7esZVxh7sTMV0xWvwFLwTT4LTlEJZsLBs637n-Or6VNVzgl8TjNs3GWMqZI1JWZzJtqYPql3SlGuLO_nw7tzinepJzpcYk4528nG1wwhtOGnkbvXjnc8mXkHaIh0sWicwgw_e6AGZpU7ajJD8tR59DCg69Il0x5_PT2vaUPwKaRTg61gvIECakVFv0PnRBRqLEhJyMaFxCUjnDDmvIIyTyQSt9biMQ1xskQ_oYLhegl9B-vnte0bWZ9AZbvqJRZ0mQZwEHvLT6pHTQ4Znt_te9fH46OLwpD778P708OCsJlyKsQbbQ2Ms7mVHetYTZgVpe0E5l5Z3bSM7Qx0RVgDhxIlWMC21EIT2urdWarxXvZ1915t-BdaU1pMe1Dr5lU5bFbVX9yvBL9UiXqmmaVqOu2JwMhvENQTtE9zT2gCjilbRplWcY250K1zXcGOEYc643knmnBFAO1us9m97SfHLBvKoVuXTYBh0gLjJilJBCGZtxwr68h_0Mm5SKJOaKMw4K2Ch6EyZFHNO4O56I1hN0VJztFSJlrqJlqJF9OLvidxJfmepAGwGcimFBaQ_b__H9hcB99zp
startdate20190701
enddate20190701
creator
0Kroth, Heiko
1Oden, Felix
2Molette, Jerome
3Schieferstein, Hanno
4Capotosti, Francesca
5Mueller, Andre
6Berndt, Mathias
7Schmitt-Willich, Heribert
8Darmency, Vincent
9Gabellieri, Emanuele
10Boudou, Cédric
11Juergens, Tanja
12Varisco, Yvan
13Vokali, Efthymia
14Hickman, David T
15Tamagnan, Gilles
16Pfeifer, Andrea
17Dinkelborg, Ludger
18Muhs, Andreas
19Stephens, Andrew
general
0Springer Berlin Heidelberg
1Springer Nature B.V
scope
0NPM
1AAYXX
2CITATION
33V.
47RV
57TK
67X7
77XB
888E
98AO
108FE
118FG
128FH
138FI
148FJ
158FK
16ABUWG
17ARAPS
18AZQEC
19BBNVY
20BENPR
21BGLVJ
22BHPHI
23DWQXO
24FYUFA
25GHDGH
26GNUQQ
27HCIFZ
28K9.
29KB0
30LK8
31M0S
32M1P
33M7P
34NAPCQ
35P5Z
36P62
37PQEST
38PQQKQ
39PQUKI
40PRINS
417X8
42BOBZL
43CLFQK
445PM
orcididhttps://orcid.org/0000-0001-5052-6586
sort
creationdate20190701
titleDiscovery 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
authorKroth, Heiko ; Oden, Felix ; Molette, Jerome ; Schieferstein, Hanno ; Capotosti, Francesca ; Mueller, Andre ; Berndt, Mathias ; Schmitt-Willich, Heribert ; Darmency, Vincent ; Gabellieri, Emanuele ; Boudou, Cédric ; Juergens, Tanja ; Varisco, Yvan ; Vokali, Efthymia ; Hickman, David T ; Tamagnan, Gilles ; Pfeifer, Andrea ; Dinkelborg, Ludger ; Muhs, Andreas ; Stephens, Andrew
facets
frbrtype5
frbrgroupidcdi_FETCH-LOGICAL-1495t-edbe6cd0b981b3b13d517b52449d487698c2f15d5e141f5753a9a5512babdd9a0
rsrctypearticles
prefilterarticles
languageeng
creationdate2019
topic
0Affinity
1Aggregates
2Alzheimer's disease
3Amine oxidase (flavin-containing)
4Autoradiography
5Binding
6Brain
7Brain slice preparation
8Cardiology
9Cognitive ability
10emission tomography
11Fluorine
12Fluorine-18
13Imaging
14Indoles
15Medicine
16Medicine & Public Health
17Neurodegenerative diseases
18Neurofibrillary tangles
19Nuclear Medicine
20Oncology
21Original
22Original Article
23Orthopedics
24Paralysis
25Pathology
26PET
27PET tracer
28PI-2620
29Positron
30Positron emission
31Positron emission tomography
32Primates
33Progressive supranuclear palsy
34Radiology
35Selectivity
36Tau
37Tau protein
38Tauopathies
39Tomography
40Tracers
41Translational research
toplevelpeer_reviewed
creatorcontrib
0Kroth, Heiko
1Oden, Felix
2Molette, Jerome
3Schieferstein, Hanno
4Capotosti, Francesca
5Mueller, Andre
6Berndt, Mathias
7Schmitt-Willich, Heribert
8Darmency, Vincent
9Gabellieri, Emanuele
10Boudou, Cédric
11Juergens, Tanja
12Varisco, Yvan
13Vokali, Efthymia
14Hickman, David T
15Tamagnan, Gilles
16Pfeifer, Andrea
17Dinkelborg, Ludger
18Muhs, Andreas
19Stephens, Andrew
collection
0PubMed
1CrossRef
2ProQuest Central (Corporate)
3Nursing & Allied Health Database
4Neurosciences Abstracts
5Health & Medical Collection
6ProQuest Central (purchase pre-March 2016)
7Medical Database (Alumni Edition)
8ProQuest Pharma Collection
9ProQuest SciTech Collection
10ProQuest Technology Collection
11ProQuest Natural Science Collection
12Hospital Premium Collection
13Hospital Premium Collection (Alumni Edition)
14ProQuest Central (Alumni) (purchase pre-March 2016)
15ProQuest Central (Alumni Edition)
16Advanced Technologies & Aerospace Collection
17ProQuest Central Essentials
18Biological Science Collection
19ProQuest Central
20Technology Collection
21Natural Science Collection
22ProQuest Central Korea
23Health Research Premium Collection
24Health Research Premium Collection (Alumni)
25ProQuest Central Student
26SciTech Premium Collection
27ProQuest Health & Medical Complete (Alumni)
28Nursing & Allied Health Database (Alumni Edition)
29ProQuest Biological Science Collection
30Health & Medical Collection (Alumni Edition)
31Medical Database
32Biological Science Database
33Nursing & Allied Health Premium
34Advanced Technologies & Aerospace Database
35ProQuest Advanced Technologies & Aerospace Collection
36ProQuest One Academic Eastern Edition
37ProQuest One Academic
38ProQuest One Academic UKI Edition
39ProQuest Central China
40MEDLINE - Academic
41OpenAIRE (Open Access)
42OpenAIRE
43PubMed Central (Full Participant titles)
jtitleEuropean Journal of Nuclear Medicine and Molecular Imaging
delivery
delcategoryRemote Search Resource
fulltextno_fulltext
addata
au
0Kroth, Heiko
1Oden, Felix
2Molette, Jerome
3Schieferstein, Hanno
4Capotosti, Francesca
5Mueller, Andre
6Berndt, Mathias
7Schmitt-Willich, Heribert
8Darmency, Vincent
9Gabellieri, Emanuele
10Boudou, Cédric
11Juergens, Tanja
12Varisco, Yvan
13Vokali, Efthymia
14Hickman, David T
15Tamagnan, Gilles
16Pfeifer, Andrea
17Dinkelborg, Ludger
18Muhs, Andreas
19Stephens, Andrew
formatjournal
genrearticle
ristypeJOUR
atitleDiscovery 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
jtitleEuropean Journal of Nuclear Medicine and Molecular Imaging
stitleEur J Nucl Med Mol Imaging
addtitleEur J Nucl Med Mol Imaging
date2019-07-01
risdate2019
volume46
issue10
spage2178
epage2189
pages2178-2189
issn1619-7070
eissn1619-7089
abstractPurpose 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.
copBerlin/Heidelberg
pubSpringer Berlin Heidelberg
pmid31264169
doi10.1007/s00259-019-04397-2
orcididhttps://orcid.org/0000-0001-5052-6586
oafree_for_read