Identification of a major radiometabolite of [ 11 C]PBB3

Hashimoto, H.; Kawamura, Kazunori; Takei, Makoto; Igarashi, Nobuyuki; Fujishiro, Tomoya; Shiomi, Satoshi; Watanabe, Rikiya; Muto, Masatoshi; Furutsuka, Kenji; Ito, Takehito; Yamasaki, Tomoteru; Yui, Joji; Nemoto, Kazuyoshi; Kimura, Yasuyuki; Higuchi, Makoto; Zhang, Ming‐Rong

doi:10.1016/j.nucmedbio.2015.08.006

Cited by 38 publications

(19 citation statements)

References 16 publications

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“…THK5351 has no known brain-penetrating metabolites [33] that would affect quantification of the tracer’s binding, but this is not the case for PBB3, which shows such a radiometabolite [23, 34]. Interestingly, however, it has been shown that PBB3 binding can be accurately quantified with simplified reference models, despite the presence of the metabolite, as illustrated using arterial sampling to obtain the parent and metabolite input functions [30].…”

Section: Methodsmentioning

confidence: 99%

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Chiotis

Stenkrona

Almkvist

et al. 2018

Eur J Nucl Med Mol Imaging

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PurposeSeveral tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design.MethodsNine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment.ResultsThe load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding.ConclusionThis research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.Electronic supplementary materialThe online version of this article (10.1007/s00259-018-4012-5) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Chiotis

Stenkrona

Almkvist

et al. 2018

Eur J Nucl Med Mol Imaging

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“…Additionally, some first-generation tau PET ligands have suffered from lack of specificity for tau (15,16), nonpolar radiometabolites (17), and off-target binding that interferes with regions of interest for monitoring early-stage tau deposition such as the hippocampus (12). Recently, [ 18…”

Section: Introductionmentioning

confidence: 99%

In vivo characterization and quantification of neurofibrillary tau PET radioligand [¹⁸F]MK-6240 in humans from Alzheimer’s disease dementia to young controls

Betthauser

Cody

Zammit

et al. 2018

Preprint

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Tau positron emission tomography (PET) imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer's disease (AD). This work investigates in vivo kinetics, quantification strategies and imaging characteristics of a novel tau PET radioligand [ 18 F]MK-6240 in humans. Methods Fifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted magnetic resonance imaging (MRI), and [ 11 C]PiB and [ 18 F]MK-6240 PET imaging. PET data were coregistered to the MRI and time-activity curves were extracted from regions of interest to assess [ 18 F]MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis (LGA) and multilinear reference tissue method (MRTM2)) were investigated for quantification of [ 18 F]MK-6240 distribution volume ratios (DVRs) in a subset of nineteen participants. Stability of DVR methods was evaluated using truncated scan durations. Standard uptake value ratio (SUVR) estimates were compared to DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature. Results Standard uptake values in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared to MRTM2. DVR estimates remained stable when truncating the scan duration to 60 minutes. SUVR determined 70-90 minutes post-injection of [ 18 F]MK-6240 indicated linearity near unity when compared to DVR estimates and minimized potential spill-in from uptake outside of the brain. [ 18 F]MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus. Conclusions [ 18 F]MK-6240 is a promising PET radioligand for in vivoimaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.

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“…Although these studies highlight the promise for tau imaging, they primarily focus on comparing clinically impaired individuals with cognitively healthy controls and do not address the potential of these ligands for identifying tau in early-stage disease where disease intervention is likely to be more effective. Additionally, some tau PET ligands have suffered from lack of specificity for tau (THK series) (15,16), nonpolar radiometabolites (PBB3) (17), and off-target binding that interferes with regions of interest for monitoring early-stage tau deposition such as the hippocampus (AV-1451 and THK series) (12). Recently, 18 F-MK-6240 has shown high in vitro affinity for NFTs and no in vivo off-target binding in the basal ganglia in nonhuman primates (18).…”

mentioning

confidence: 99%

In Vivo Characterization and Quantification of Neurofibrillary Tau PET Radioligand ¹⁸F-MK-6240 in Humans from Alzheimer Disease Dementia to Young Controls

Betthauser¹,

Cody²,

Zammit³

et al. 2018

J Nucl Med

186

141

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Tau positron emission tomography (PET) imaging has potential for elucidating changes in the deposition of neuropathological tau aggregates that are occurring during the progression of Alzheimer's disease (AD). This work investigates in vivo kinetics, quantification strategies and imaging characteristics of a novel tau PET radioligand [F]MK-6240 in humans. Fifty-one individuals ranging from cognitively normal young controls to persons with dementia underwent T1-weighted magnetic resonance imaging (MRI), and [C]PiB and [F]MK-6240 PET imaging. PET data were coregistered to the MRI and time-activity curves were extracted from regions of interest to assess [F]MK-6240 kinetics. The pons and inferior cerebellum were investigated as potential reference regions. Reference tissue methods (Logan graphical analysis (LGA) and multilinear reference tissue method (MRTM2)) were investigated for quantification of [F]MK-6240 distribution volume ratios (DVRs) in a subset of nineteen participants. Stability of DVR methods was evaluated using truncated scan durations. Standard uptake value ratio (SUVR) estimates were compared to DVR estimates to determine the optimal timing window for SUVR analysis. Parametric SUVR images were used to identify regions of potential off-target binding and to compare binding patterns with neurofibrillary tau staging established in neuropathology literature. Standard uptake values in the pons and the inferior cerebellum indicated consistent clearance across all 51 subjects. LGA and MRTM2 DVR estimates were similar, with LGA slightly underestimating DVR compared to MRTM2. DVR estimates remained stable when truncating the scan duration to 60 minutes. SUVR determined 70-90 minutes post-injection of [F]MK-6240 indicated linearity near unity when compared to DVR estimates and minimized potential spill-in from uptake outside of the brain. [F]MK-6240 binding patterns in target regions were consistent with neuropathological neurofibrillary tau staging. Off-target binding regions included the ethmoid sinus, clivus, meninges, substantia nigra, but not the basal ganglia or choroid plexus. [F]MK-6240 is a promising PET radioligand for in vivo imaging of neurofibrillary tau aggregates in AD with minimal off-target binding in the human brain.

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Identification of a major radiometabolite of [ 11 C]PBB3

Cited by 38 publications

References 16 publications

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

In vivo characterization and quantification of neurofibrillary tau PET radioligand [¹⁸F]MK-6240 in humans from Alzheimer’s disease dementia to young controls

In Vivo Characterization and Quantification of Neurofibrillary Tau PET Radioligand ¹⁸F-MK-6240 in Humans from Alzheimer Disease Dementia to Young Controls

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Identification of a major radiometabolite of [ 11 C]PBB3

Cited by 38 publications

References 16 publications

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

In vivo characterization and quantification of neurofibrillary tau PET radioligand [18F]MK-6240 in humans from Alzheimer’s disease dementia to young controls

In Vivo Characterization and Quantification of Neurofibrillary Tau PET Radioligand 18F-MK-6240 in Humans from Alzheimer Disease Dementia to Young Controls

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Product

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In vivo characterization and quantification of neurofibrillary tau PET radioligand [¹⁸F]MK-6240 in humans from Alzheimer’s disease dementia to young controls

In Vivo Characterization and Quantification of Neurofibrillary Tau PET Radioligand ¹⁸F-MK-6240 in Humans from Alzheimer Disease Dementia to Young Controls