Delving into the Latest Updates on [18F]THK-5351 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug, Diagnostic radiopharmaceuticals

Synonyms

FluoroTau

+ [4]

Target

TAU

Action

inhibitors

Mechanism

TAU inhibitors(Microtubule-associated protein tau inhibitors)

Therapeutic Areas

Nervous System DiseasesOther Diseases

Active Indication

Cognitive DysfunctionNeuroinflammation

Inactive Indication

Alzheimer DiseaseDementiaDepressive Disorder, Major+ [5]

Originator Organization

Tohoku University

Active Organization

Chang Gung Memorial Hospital

Inactive Organization

Asan Medical CenterThe Asan Foundation

Tohoku University

License Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC18H18FN3O2

InChIKeyDLVXFZWSPCOWSN-DHZJDKHOSA-N

CAS Registry1707148-68-2

Background and objects： Neuroinflammation is an active process detectable in the earliest stages of the neurodegeneration pathway. On the other hand, significant neuroinflammation, such as reactive astrocytosis, can also be observed after cerebral ischemic injury. [18F]THK5351 can monitor the neuroinflammatory process due to its high affinity to astrogliosis, and [18F]PMPBB3 is the novel tau protein radiotracer without significant off-target binding to MAO-B. The investigators hypothesize that the neuroinflammation after acute stroke may induce the tau protein accumulation. In the current proposal, our aims are to 1) explore the interaction between neuroinflammation and tau protein accumulation in acute stroke patients by applying both the [18F]PMPBB3 and [18F]THK5351 PET images and 2) determine their influence on the longterm stroke outcome and cognitive performance.
Method： The prospective project plans to recruit 2 groups of participants: one is patients with first-ever acute stroke (Group A, n=50), and the other is healthy people as the control group (Group B, n=30). Within 3 weeks of stroke, [18F]THK5351 and [18F]PMPBB3 PET will be done for imaging cerebral neuroinflammation and tau protein distribution. Brain MRI for obtaining structural and functional information will be done within 3 weeks and 3 months after stroke. Clinical and cognitive outcome will be evaluated at week 3 and months 3 and 12. In addition, APOE genotyping and carotid ultrasound will be performed as well. By obtaining the neuroimaging information, such as severity of white matter change and infarction, cortical and hippocampal atrophy, and SUVRs of [18F]THK5351 and [18F]PMPBB3 PET, the study will be able to investigate the complex interaction between neuroinflammation and tau protein accumulation after stroke, and also evaluate their influence on structural changes, stroke outcome and cognitive performance. Group comparisons will be performed using the Chi-square test, independent t test, Mann-Whitney U test, and multiple linear regression, where appropriate.
Anticipation： In this project, the investigators will be able to identify the distribution patterns of neuroinflammation and tau protein accumulation after actue stroke. Secondly, the investigators expect that the presence of neuroinflammation and tau protein accumulation will interfere with the functional connectivity. Finally, the investigators expect that the extent of neuroinflammation and tau protein is correlated with stroke outcome and post-stroke cognitive impairment.

Start Date01 Nov 2020

Sponsor / Collaborator

Chang Gung Memorial Hospital

100 Clinical Results associated with [18F]THK-5351

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100 Translational Medicine associated with [18F]THK-5351

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100 Patents (Medical) associated with [18F]THK-5351

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50

Literatures (Medical) associated with [18F]THK-5351

01 Jan 2024·Yonsei Medical Journal

Diverging Relationships among Amyloid, Tau, and Brain Atrophy in Early-Onset and Late-Onset Alzheimer’s Disease

Article

Author: Seo, Seongho ; Noh, Young ; Seong, Joon-Kyung ; Shin, Jeong-Hyeon ; Lee, Sang-Yoon ; Cho, Jaelim ; Okamura, Nobuyuki ; Byun, Justin ; Kang, Jae Myeong ; Kim, Woo-Ram ; Na, Han Kyu ; Kim, Sung-Woo

PURPOSEAlzheimer's disease (AD) dementia may not be a single disease entity. Early-onset AD (EOAD) and late-onset AD (LOAD) have been united under the same eponym of AD until now, but disentangling the heterogeneity according to the age of sonset has been a major tenet in the field of AD research.MATERIALS AND METHODSNinety-nine patients with AD (EOAD, n=54; LOAD, n=45) and 66 cognitively normal controls completed both [¹⁸F]THK5351 and [¹⁸F]flutemetamol (FLUTE) positron emission tomography scans along with structural magnetic resonance imaging and detailed neuropsychological tests.RESULTSEOAD patients had higher THK retention in the precuneus, parietal, and frontal lobe, while LOAD patients had higher THK retention in the medial temporal lobe. Intravoxel correlation analyses revealed that EOAD presented narrower territory of local FLUTE-THK correlation, while LOAD presented broader territory of correlation extending to overall parieto-occipito-temporal regions. EOAD patients had broader brain areas which showed significant negative correlations between cortical thickness and THK retention, whereas in LOAD, only limited brain areas showed significant correlation with THK retention. In EOAD, most of the cognitive test results were correlated with THK retention. However, a few cognitive test results were correlated with THK retention in LOAD.CONCLUSIONLOAD seemed to show gradual increase in tau and amyloid, and those two pathologies have association to each other. On the other hand, in EOAD, tau and amyloid may develop more abruptly and independently. These findings suggest LOAD and EOAD may have different courses of pathomechanism.

01 Nov 2023·Nagoya journal of medical science

＜Editors' Choice＞ Pattern of THK 5351 retention in normal aging involves core regions of resting state networks associated with higher cognitive function.

Article

Author: Kato, Toshiyasu ; Naganawa, Shinji ; Bagarinao, Epifanio ; Kato, Katsuhiko ; Watanabe, Hirohisa ; Katsuno, Masahisa ; Yokoi, Takamasa ; Yamaguchi, Hiroshi ; Ogura, Aya ; Kawabata, Kazuya ; Hara, Kazuhiro ; Yanai, Kazuhiko ; Sobue, Gen ; Okamura, Nobuyuki ; Masuda, Michihito ; Ohdake, Reiko ; Yoshida, Yusuke

We aimed to elucidate the distribution pattern of the positron emission tomography probe [18F]THK 5351, a marker for astrogliosis and tau accumulation, in healthy aging. We also assessed the relationship between THK5351 retention and resting state networks. We enrolled 62 healthy participants in this study. All participants underwent magnetic resonance imaging/positron emission tomography scanning consisting of T1-weighted images, resting state functional magnetic resonance imaging, Pittsburgh Compound-B and THK positron emission tomography. The preprocessed THK images were entered into a scaled subprofile modeling/principal component analysis to extract THK distribution patterns. Using the most significant THK pattern, we generated regions of interest, and performed seed-based functional connectivity analyses. We also evaluated the functional connectivity overlap ratio to identify regions with high between-network connectivity. The most significant THK distributions were observed in the medial prefrontal cortex and bilateral putamen. The seed regions of interest in the medial prefrontal cortex had a functional connectivity map that significantly overlapped with regions of the dorsal default mode network. The seed regions of interest in the putamen showed strong overlap with the basal ganglia and anterior salience networks. The functional connectivity overlap ratio also showed that three peak regions had the characteristics of connector hubs. We have identified an age-related spatial distribution of THK in the medial prefrontal cortex and basal ganglia in normal aging. Interestingly, the distribution's peaks are located in regions of connector hubs that are strongly connected to large-scale resting state networks associated with higher cognitive function.

01 Sep 2023·Annals of nuclear medicine

Toward standardization of tau PET imaging corresponding to various tau PET tracers: a multicenter phantom study.

Article

Author: Wagatsuma, Kei ; Yamao, Tensho ; Matsuda, Hiroshi ; Miwa, Kenta ; Sakurai, Minoru ; Fujita, Naotoshi ; Ishii, Kenji ; Akamatsu, Go ; Hanaoka, Kohei ; Kamitaka, Yuto

OBJECTIVETau positron emission tomography (PET) imaging is a recently developed non-invasive tool that can detect the density and extension of tau neurofibrillary tangles. Tau PET tracers have been validated to harmonize and accelerate their development and implementation in clinical practice. Whereas standard protocols including injected dose, uptake time, and duration have been determined for tau PET tracers, reconstruction parameters have not been standardized. The present study conducted phantom experiments based on tau pathology to standardize quantitative tau PET imaging parameters and optimize reconstruction conditions of PET scanners at four Japanese sites according to the results of phantom experiments.METHODSThe activity of 4.0 and 2.0 kBq/mL for Hoffman 3D brain and cylindrical phantoms, respectively, was estimated from published studies of brain activity using [¹⁸F]flortaucipir, [¹⁸F]THK5351, and [¹⁸F]MK6240. We developed an original tau-specific volume of interest template for the brain based on pathophysiological tau distribution in the brain defined as Braak stages. We acquired brain and cylindrical phantom images using four PET scanners. Iteration numbers were determined as contrast and recover coefficients (RCs) in gray (GM) and white (WM) matter, and the magnitude of the Gaussian filter was determined from image noise.RESULTSContrast and RC converged at ≥ 4 iterations, the error rates of RC for GM and WM were < 15% and 1%, respectively, and noise was < 10% in Gaussian filters of 2-4 mm in images acquired using the four scanners. Optimizing the reconstruction conditions for phantom tau PET images acquired by each scanner improved contrast and image noise.CONCLUSIONSThe phantom activity was comprehensive for first- and second-generation tau PET tracers. The mid-range activity that we determined could be applied to later tau PET tracers. We propose an analytical tau-specific VOI template based on tau pathophysiological changes in patients with AD to standardize tau PET imaging. Phantom images reconstructed under the optimized conditions for tau PET imaging achieved excellent image quality and quantitative accuracy.

100 Deals associated with [18F]THK-5351

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cognitive Dysfunction	Phase 2	Taiwan Province	Chang Gung Memorial Hospital	01 Nov 2020
Neuroinflammation	Phase 2	Taiwan Province	Chang Gung Memorial Hospital	01 Nov 2020
Depressive Disorder, Major	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	23 Mar 2018
Parkinson Disease	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	31 Jul 2017
Supranuclear Palsy, Progressive	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	31 Jul 2017
Alzheimer Disease	Preclinical	United States	Asan Medical Center	11 Jan 2016
Dementia	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	04 Jan 2016
Mild cognitive disorder	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	04 Jan 2016
Plaque, Amyloid	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	04 Jan 2016
Stroke	Preclinical	Taiwan Province	Chang Gung Memorial Hospital	04 Jan 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


EANM2019	Not Applicable	-	-	[18F]-THK5351	quybwayowv(axwaggpxxi) = yuatfhlbax okcqsbbgke (haoutrqruf, 11.6)	-	18 Sep 2019
NCT02884492 (CTgov)	Phase 2	Alzheimer Disease	17	Lumbar Puncture (optional)+18F-THK-5351 (Cognitive Impairment)	mprlzujeta(aeyaiwdcdy) = eatvjqjuqf fndiqwkgvk (tfxpbbsspb, kxmjkfluab - wrdpgqulqh) View more	-	19 Nov 2018
NCT02884492 (CTgov)	Phase 2	Alzheimer Disease	17	Lumbar Puncture (optional)+18F-THK-5351 (No Cognitive Impairment)	mprlzujeta(aeyaiwdcdy) = hrtmsfqrgc fndiqwkgvk (tfxpbbsspb, wbxlnbtser - mfpvzsrajh) View more	-	19 Nov 2018
AAIC2018	Not Applicable	-	-	THK5351 and its derivatives	rbzmmuasok(eifzxvgdmk) = upsbxiplcx gkhbmtvkzl (yyajoushsg )	-	01 Jul 2018
NCT02686216 (Pubmed \| J Nucl Med)	Phase 1	-	12	<sup>18</sup>F-THK-5351	rxpzzfxach(dpjzostoad) = twybyjzmoy jhlzfretrp (xyszwcdtbr )	-	01 Sep 2017
AAIC2017	Not Applicable	Alzheimer Disease	-	THK-5351 (Normal controls (NC))	ytppckmlne(ufjimgdasn) = pvqaaupzim fldrxfzhlq (lsyswvjfkb )	-	01 Jul 2017
AAIC2017	Not Applicable	Alzheimer Disease	-	THK-5351 (Mild cognitive impairment (MCI))	ytppckmlne(ufjimgdasn) = iibqirdgkj fldrxfzhlq (lsyswvjfkb )	-	01 Jul 2017
AAIC2017	Not Applicable	-	-	THK5351	pyjxfbntkh(mdgsmmrzgc) = idjzlogadz zucawdjgvm (mdtztcgylc )	-	01 Jul 2017
AAIC2016	Not Applicable	-	7	18F-THK-5351	pkrxxkqtyo(voqafkghxn) = nipgknvbnt qaplxvlcdw (kibvzssawc )	-	01 Jul 2016