André Manook | Technische Universität München (original) (raw)
Papers by André Manook
ACS Chemical Neuroscience, 2015
Imidazo[2,1-b]benzothiazoles (IBTs) are a promising novel class of amyloid positron emission tomo... more Imidazo[2,1-b]benzothiazoles (IBTs) are a promising novel class of amyloid positron emission tomography (PET) radiopharmaceuticals for diagnosis of neurodegenerative disorders like Alzheimer's disease (AD). Their good in vivo imaging properties have previously been shown in preclinical studies. Among IBTs, fluorinated [(18)F]FIBT was selected for further characterization and advancement toward use in humans. [(18)F]FIBT characteristics were analyzed in relation to Pittsburgh compound B (PiB) as reference ligand. [(18)F]FIBT and [(3)H]PiB were coinjected to an APP/PS1 mouse for ex vivo dual-label autoradiographic correlation. Acute dose toxicity of FIBT was examined in two groups of healthy mice. Preexisting in vivo stability and biodistribution studies in mice were complemented with analogous studies in rats. [(18)F]FIBT was titrated against postmortem human AD brain homogenate in a saturation binding assay previously performed with [(3)H]PiB. Binding of [(18)F]FIBT to human AD brain was further analyzed by in vitro incubation of human AD brain sections in comparison to [(11)C]PiB in relation to standard immunohistochemistry. Finally, [(18)F]FIBT was administered to two human subjects for a dynamic 90 min PET/MR brain investigation. Ex vivo autoradiography confirmed good uptake of [(18)F]FIBT to mouse brain and its excellent correlation to [(3)H]PiB binding. No toxicity of FIBT could be found in mice at a concentration of 33.3 nmol/kg. As in mice, [(18)F]FIBT was showing high in vivo stability in rats and comparable regional brain biodistribution dynamics to [(3)H]PiB. Radioligand saturation binding confirmed at least one high-affinity binding component of [(18)F]FIBT around 1 nM. Good binding of FIBT relative to PiB was further confirmed in binding assays and autoradiographies using post-mortem AD brain. First use of [(18)F]FIBT in humans successfully yielded clinical [(18)F]FIBT PET/MR images with very good contrast. In summary, [(18)F]FIBT has been characterized to be a new lead compound with improved binding characteristics and pharmacokinetics on its own as well as in comparison to PiB. A pilot human PET investigation provided high-quality images with a plausible tracer distribution pattern. Detailed clinical investigations are needed to confirm these first results and to explore the specific qualities of [(18)F]FIBT PET for dementia imaging in relation to established ligands.
PLoS ONE, 2009
Background: Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS... more Background: Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral b-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.
![Research paper thumbnail of Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease](https://attachments.academia-assets.com/45551981/thumbnails/1.jpg)
](PLoS ONE, 2012
In vivo imaging and quantification of amyloid-b plaque (Ab) burden in small-animal models of Alzh... more In vivo imaging and quantification of amyloid-b plaque (Ab) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Ab in mouse brain with [ 11 C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Ab at different disease stages in homozygous and hemizygous animals. We performed multi-modal crossvalidations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [ 11 C]PiB uptake in individual brain regions with Ab deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Ab pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [ 11 C]PiB imaging of Ab in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Ab imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice. Citation: Manook A, Yousefi BH, Willuweit A, Platzer S, Reder S, et al. (2012) Small-Animal PET Imaging of Amyloid-Beta Plaques with [ 11 C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease. PLoS ONE 7(3): e31310.
Journal of Medicinal Chemistry, 2011
We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imag... more We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aβ. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aβ plaques.
Alzheimer's & Dementia, 2013
ACS Medicinal Chemistry Letters, 2011
(18)F-labeled imidazo[2,1-b]benzothiazole ([(18)F]8) was synthesized and evaluated as a tracer fo... more (18)F-labeled imidazo[2,1-b]benzothiazole ([(18)F]8) was synthesized and evaluated as a tracer for cerebral β-amyloid deposits (Aβ) by means of positron emission tomography (PET). [(18)F]8 exhibits a high affinity to Aβ and suitable brain uptake kinetics combined with a high metabolic stability in the brain. In a double transgenic APP/PS1 mouse model of Alzheimer's disease, we demonstrated a specific uptake of [(18)F]8 in Aβ-containing telencephalic brain regions. The specific binding of [(18)F]8 to Aβ was confirmed by regional brain biodistribution and autoradiography and correlated to immunohistochemistry staining. Analysis of brain sections of APP/PS1 mouse injected with a cocktail of [(18)F]8 and reference compound [(3)H]PiB revealed that the two tracers bind to Aβ plaques in the brain of mouse in a comparable binding pattern. [(18)F]8 represents the first high-contrast PET imaging agent for detection of Aβ plaques in transgenic mouse model of Alzheimer's disease and holds promise for transfer to a clinical evaluation.
EJNMMI research, 2015
Over the last decade, an increasing number of studies have been published on the use of amyloid-β... more Over the last decade, an increasing number of studies have been published on the use of amyloid-β (Aβ) PET imaging with different (18)F-radiopharmaceuticals for clinical characterization of Alzheimer's disease (AD) in different stages. However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers. Thus, the aim of this study was the direct intra-individual in vivo comparison of different Aβ-targeted radiopharmaceuticals for PET imaging, including the newly developed agent [(18)F]FIBT. A small group of four animals of a well-characterized APP/PS1 transgenic (tg) mouse model of AD and gender-matched control (ctl) animals underwent a sequential and standardized PET imaging regimen for direct comparison of [(18)F]FIBT, [(18)F]florbetaben, and [(11)C]PiB. The quantitative PET imaging data were cross-validated with the cerebral Aβ plaque load as quantified ex vivo on histological sections. We found that FIBT...
ACS Chemical Neuroscience, 2015
Imidazo[2,1-b]benzothiazoles (IBTs) are a promising novel class of amyloid positron emission tomo... more Imidazo[2,1-b]benzothiazoles (IBTs) are a promising novel class of amyloid positron emission tomography (PET) radiopharmaceuticals for diagnosis of neurodegenerative disorders like Alzheimer's disease (AD). Their good in vivo imaging properties have previously been shown in preclinical studies. Among IBTs, fluorinated [(18)F]FIBT was selected for further characterization and advancement toward use in humans. [(18)F]FIBT characteristics were analyzed in relation to Pittsburgh compound B (PiB) as reference ligand. [(18)F]FIBT and [(3)H]PiB were coinjected to an APP/PS1 mouse for ex vivo dual-label autoradiographic correlation. Acute dose toxicity of FIBT was examined in two groups of healthy mice. Preexisting in vivo stability and biodistribution studies in mice were complemented with analogous studies in rats. [(18)F]FIBT was titrated against postmortem human AD brain homogenate in a saturation binding assay previously performed with [(3)H]PiB. Binding of [(18)F]FIBT to human AD brain was further analyzed by in vitro incubation of human AD brain sections in comparison to [(11)C]PiB in relation to standard immunohistochemistry. Finally, [(18)F]FIBT was administered to two human subjects for a dynamic 90 min PET/MR brain investigation. Ex vivo autoradiography confirmed good uptake of [(18)F]FIBT to mouse brain and its excellent correlation to [(3)H]PiB binding. No toxicity of FIBT could be found in mice at a concentration of 33.3 nmol/kg. As in mice, [(18)F]FIBT was showing high in vivo stability in rats and comparable regional brain biodistribution dynamics to [(3)H]PiB. Radioligand saturation binding confirmed at least one high-affinity binding component of [(18)F]FIBT around 1 nM. Good binding of FIBT relative to PiB was further confirmed in binding assays and autoradiographies using post-mortem AD brain. First use of [(18)F]FIBT in humans successfully yielded clinical [(18)F]FIBT PET/MR images with very good contrast. In summary, [(18)F]FIBT has been characterized to be a new lead compound with improved binding characteristics and pharmacokinetics on its own as well as in comparison to PiB. A pilot human PET investigation provided high-quality images with a plausible tracer distribution pattern. Detailed clinical investigations are needed to confirm these first results and to explore the specific qualities of [(18)F]FIBT PET for dementia imaging in relation to established ligands.
PLoS ONE, 2009
Background: Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS... more Background: Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral b-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues.
PLoS ONE, 2012
In vivo imaging and quantification of amyloid-b plaque (Ab) burden in small-animal models of Alzh... more In vivo imaging and quantification of amyloid-b plaque (Ab) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Ab in mouse brain with [ 11 C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Ab at different disease stages in homozygous and hemizygous animals. We performed multi-modal crossvalidations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [ 11 C]PiB uptake in individual brain regions with Ab deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Ab pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [ 11 C]PiB imaging of Ab in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Ab imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice. Citation: Manook A, Yousefi BH, Willuweit A, Platzer S, Reder S, et al. (2012) Small-Animal PET Imaging of Amyloid-Beta Plaques with [ 11 C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease. PLoS ONE 7(3): e31310.
Journal of Medicinal Chemistry, 2011
We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imag... more We report a novel series of (11)C-labeled imidazo[2,1-b]benzothiazoles (IBTs) as tracers for imaging of cerebral β-amyloid (Aβ) deposits in patients with Alzheimer's disease (AD) by means of positron emission tomography (PET). From a series of 11 compounds, candidates were identified to have a high binding affinity for Aβ. Selected compounds were prepared as O- or N-[(11)C]methyl derivatives and shown to have a high initial brain uptake in wild-type mice (range 1.9-9.2% I.D./g at 5 min). 2-(p-[(11)C]Methylaminophenyl)-7-methoxyimidazo[2,1-b] benzothiazole ([(11)C]5) was identified as a lead based on the combined favorable properties of high initial brain uptake, rapid clearance from normal brain, and high in vitro affinity for Aβ(1-40) (K(i) = 3.5 nM) and Aβ(1-42) (5.8 nM), which were superior to the Pittsburgh compound B (1a). In an APP/PS1 mouse model of AD (Tg), we demonstrate a specific uptake of [(11)C]5 in Aβ-containing telencephalic brain regions by means of small-animal PET that was confirmed by regional brain biodistribution, ex vivo autoradiography, and immunohistochemistry. Analysis of brain sections of Tg mice receiving a single bolus injection of [(11)C]5 and [(3)H]1a together revealed that the tracers bind to Aβ plaques in the brain of Tg mice in a comparable pattern. Taken together, these data suggest that IBTs represent useful PET imaging agents for high-sensitivity detection of Aβ plaques.
Alzheimer's & Dementia, 2013
ACS Medicinal Chemistry Letters, 2011
(18)F-labeled imidazo[2,1-b]benzothiazole ([(18)F]8) was synthesized and evaluated as a tracer fo... more (18)F-labeled imidazo[2,1-b]benzothiazole ([(18)F]8) was synthesized and evaluated as a tracer for cerebral β-amyloid deposits (Aβ) by means of positron emission tomography (PET). [(18)F]8 exhibits a high affinity to Aβ and suitable brain uptake kinetics combined with a high metabolic stability in the brain. In a double transgenic APP/PS1 mouse model of Alzheimer's disease, we demonstrated a specific uptake of [(18)F]8 in Aβ-containing telencephalic brain regions. The specific binding of [(18)F]8 to Aβ was confirmed by regional brain biodistribution and autoradiography and correlated to immunohistochemistry staining. Analysis of brain sections of APP/PS1 mouse injected with a cocktail of [(18)F]8 and reference compound [(3)H]PiB revealed that the two tracers bind to Aβ plaques in the brain of mouse in a comparable binding pattern. [(18)F]8 represents the first high-contrast PET imaging agent for detection of Aβ plaques in transgenic mouse model of Alzheimer's disease and holds promise for transfer to a clinical evaluation.
EJNMMI research, 2015
Over the last decade, an increasing number of studies have been published on the use of amyloid-β... more Over the last decade, an increasing number of studies have been published on the use of amyloid-β (Aβ) PET imaging with different (18)F-radiopharmaceuticals for clinical characterization of Alzheimer's disease (AD) in different stages. However, distinct study cohorts and different quantification techniques allow only for an indirect comparison between the different tracers. Thus, the aim of this study was the direct intra-individual in vivo comparison of different Aβ-targeted radiopharmaceuticals for PET imaging, including the newly developed agent [(18)F]FIBT. A small group of four animals of a well-characterized APP/PS1 transgenic (tg) mouse model of AD and gender-matched control (ctl) animals underwent a sequential and standardized PET imaging regimen for direct comparison of [(18)F]FIBT, [(18)F]florbetaben, and [(11)C]PiB. The quantitative PET imaging data were cross-validated with the cerebral Aβ plaque load as quantified ex vivo on histological sections. We found that FIBT...