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

Mechanism

TAU inhibitors(Microtubule-associated protein tau inhibitors), PET imaging(Positron-emission tomography enhancers)

Therapeutic Areas

Nervous System Diseases

Active Indication

Neuroinflammation

Inactive Indication

Alzheimer DiseaseDementiaMild cognitive disorder+ [2]

Originator Organization

Tohoku University

Active Organization

Chang Gung Memorial Hospital

Inactive Organization

Asan Medical CenterThe Asan Foundation

Tohoku University

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

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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9

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

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.

01 Jan 2022·Folia Pharmacologica Japonica

Imaging of neuropathology by PET tracers

Review

Author: Harada, Ryuichi

Alzheimer's disease (AD) is one of the most common causes of dementia in the world. Neurodegeneration, gliosis, and misfolded proteins such as amyloid plaques and tau tangles are neuropathological hallmarks in AD. In vivo imaging of these neuropathological lesions would be good biomarkers to understand pathophysiology as well as surrogate markers for clinical trials. We developed THK tau radiotracers including [¹⁸F]THK-5351 and tested them in humans. Validations studies identified monoamine oxidase-B (MAO-B) as the off-target binding substrate of [¹⁸F]THK-5351. Since the elevation of MAO-B, which is highly expressed in reactive astrocytes, were observed in various neurological conditions, MAO-B would be a promising target for imaging reactive astrogliosis. In fact, [¹⁸F]THK-5351 PET studies demonstrated that high tracer uptake in site susceptible regions to occur astrogliosis in various neurological disorders. However, the lack of binding selectivity affects the interpretation of PET images. Therefore, we performed lead optimization from [¹⁸F]THK-5351 generating a selective and reversible MAO-B PET tracer, [¹⁸F]SMBT-1. These translational and reverse translational studies, from the development of PET tracers to validation of PET images, led to the generation of new biomarkers. In this review, we will introduce the development of [¹⁸F]THK-5351, identification of off-target binding substrates, imaging-autopsy validations, new tracer development ([¹⁸F]SMBT-1), and finally recent clinical studies of [¹⁸F]SMBT-1.

01 May 2021·Seminars in Nuclear MedicineQ2 · MEDICINE

Imaging of Tau Pathology in Neurodegenerative Diseases: An Update

Q2 · MEDICINE

Review

Author: Beyer, Leonie ; Brendel, Matthias

Pathological accumulated misfolded tau underlies various neurodegenerative diseases and associated clinical syndromes. To diagnose those diseases reliable before death or even at early stages, many different tau-specific radiotracers have been developed in the last decade to be used with positron-emission-tomography. In contrast to amyloid-β imaging, different isoforms of tau exist further complicating radiotracer development. First-generation radiotracers like [¹¹C]PBB3, [¹⁸F]AV1451 and [¹⁸F]THK5351 have been extensively investigated in vitro and in vivo. In Alzheimer's disease (AD), high specific binding could be detected, and evidence of clinical applicability recently led to clinical approval of [¹⁸F]flortaucipir ([¹⁸F]AV1451) by the FDA. Nevertheless, absent or minor binding to non-AD tau isoforms and high off-target binding to non-tau brain structures limit the diagnostic applicability especially in non-AD tauopathies demanding further tracer development. In vitro assays and autoradiography results of next-generation radiotracers [¹⁸F]MK-6240, [¹⁸F]RO-948, [¹⁸F]PM-PBB3, [¹⁸F]GTP-1 and [¹⁸F]PI-2620 clearly indicate less off-target binding and high specific binding to tau neurofibrils. First in human studies have been conducted with promising results for all tracers in AD patients, and also some positive experience in non-AD tauopathies. Overall, larger scaled autoradiography and human studies are needed to further evaluate the most promising candidates and support future clinical approval.

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
Neuroinflammation	Phase 2	TW	Chang Gung Memorial Hospital	01 Nov 2020
Alzheimer Disease	Phase 1	KR	Asan Medical Center	11 Jan 2016
Dementia	Phase 1	TW	Chang Gung Memorial Hospital	04 Jan 2016
Mild cognitive disorder	Phase 1	TW	Chang Gung Memorial Hospital	04 Jan 2016
Plaque, Amyloid	Phase 1	TW	Chang Gung Memorial Hospital	04 Jan 2016
Stroke	Phase 1	TW	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


NCT02884492 (CTgov)	Phase 2	Alzheimer Disease	17	Lumbar Puncture (optional)+18F-THK-5351 (Cognitive Impairment)	glrigxwols(lxwzrjeiug) = vrseuuwgdg fcwadujpwf (iirpooedku, xbjxxcdgsh - fiqdvklktn) View more	-	19 Nov 2018
NCT02884492 (CTgov)	Phase 2	Alzheimer Disease	17	Lumbar Puncture (optional)+18F-THK-5351 (No Cognitive Impairment)	glrigxwols(lxwzrjeiug) = wiezekfzdz fcwadujpwf (iirpooedku, upmmemmpca - khxjmxiptr) View more	-	19 Nov 2018
AAIC2018	Not Applicable	-	-	THK5351 and its derivatives	uxumqiugwa(bgfxrjrifu) = xkqwvfjwok ojfundnmwq (wwtadrrnsh )	-	01 Jul 2018
NCT02686216 (Pubmed \| J Nucl Med)	Phase 1	-	12	<sup>18</sup>F-THK-5351	xzjmihjdcr(lnfbggvivx) = kkfjpspdnl gqwzzyhytb (hyucpiywrb )	-	01 Sep 2017
AAIC2017	Not Applicable	Alzheimer Disease	-	THK-5351 (Normal controls (NC))	gugdxdnllb(kculxsabzk) = fjzgmsvtzq tiawnuoypz (lfgevcntdh )	-	01 Jul 2017
AAIC2017	Not Applicable	Alzheimer Disease	-	THK-5351 (Mild cognitive impairment (MCI))	gugdxdnllb(kculxsabzk) = qltlkrudov tiawnuoypz (lfgevcntdh )	-	01 Jul 2017
AAIC2017	Not Applicable	-	-	THK5351	hduzatzzfd(ytrfxjixsd) = oszxvohyii bqvbyicrus (auyubjrkfq )	-	01 Jul 2017
AAIC2016	Not Applicable	-	7	18F-THK-5351	noulnjgxlk(oklwjaubza) = veffvmtrnh tfguukdcrd (thcdqbgziv )	-	01 Jul 2016