Radioiodinated Tau Imaging Agent III Molecular Modeling, Synthesis, and Evaluation of a New Tau Imaging Agent, [I]ISAS in Post-Mortem Human Alzheimer's Disease Brain.

Using a molecular modeling approach for Tau-binding sites, we modified our previously reported imaging agent, [I]INFT, for the potential improvement of binding properties to Tau in an Alzheimer's disease (AD) brain. Two new derivatives, namely [I]ISAS and [I]NIPZ, were designed, where binding energies at site 1 of Tau were -7.4 and -6.

[F]Flotaza for Aβ Plaque Diagnostic Imaging: Evaluation in Postmortem Human Alzheimer's Disease Brain Hippocampus and PET/CT Imaging in 5xFAD Transgenic Mice.

The diagnostic value of imaging Aβ plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [F]flotaza in transgenic 5xFAD mice expressing Aβ plaques.

Glutamate's Effects on the N-Methyl-D-Aspartate (NMDA) Receptor Ion Channel in Alzheimer's Disease Brain: Challenges for PET Radiotracer Development for Imaging the NMDA Ion Channel.

In an effort to further understand the challenges facing in vivo imaging probe development for the N-methyl-D-aspartate (NMDA) receptor ion channel, we have evaluated the effect of glutamate on the Alzheimer's disease (AD) brain. Human post-mortem AD brain slices of the frontal cortex and anterior cingulate were incubated with [H]MK-801 and adjacent sections were tested for Aβ and Tau. The binding of [H]MK-801 was measured in the absence and presence of glutamate and glycine.

Synthesis and Evaluation of Compound Targeting α7 and β2 Subunits in Nicotinic Acetylcholinergic Receptor.

Nicotinic acetylcholine receptors (nAChRs) are involved in various central nervous system functions and have also been implicated in several neurodegenerative disorders. The heteromeric α4β2* and homomeric α7 are two major nAChR subtypes which have been studied in the brain using positron emission tomography (PET). Our comparative autoradiographic studies of the two receptor types in the mouse and rat brains show major differences in the thalamus (α4β2* >> α7), hippocampus (α7 >> α4β2*), and subiculum (α4β2* >> α7).

Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice.

Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [F]Nifene, displaying similar pKa and binding affinity to nicotine.

A simplified protocol for the automated production of 2-[ F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine ([ F]nifene) on an IBA Synthera® module.

The α4β2 nicotinic acetylcholine receptor (nAChR) ligand 2-[ F]fluoro-3-[2-((S)-3-pyrrolinyl)methoxy]pyridine ([ F]nifene) has been synthesized in 10% decay-corrected radiochemical yield using the IBA Synthera® platform (IBA Cyclotron Solutions, Louvain-la-Neuve, Belgium) with an integrated fluidic processor (IFP). Boc-nitronifene served as the precursor, and 20% trifluoroacetic acid (TFA) was used to deprotect the Boc-group after radiolabeling. By omitting the solvent extraction step after radiolabeling, the process was simplified to a single step with no manual intervention.

[I]INFT: Synthesis and Evaluation of a New Imaging Agent for Tau Protein in Post-Mortem Human Alzheimer's Disease Brain.

Aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) is a neuropathological feature in Alzheimer's disease (AD). This study aimed to develop and evaluate the effectiveness of a novel radioiodinated tracer, 4-[I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)pyridine ([I]INFT), for binding to Tau protein in postmortem human AD brain. Radiosynthesis of [I]INFT was carried out using electrophilic destannylation by iodine-125 and purified chromatographically.

Comparison of Monoamine Oxidase-A, Aβ Plaques, Tau, and Translocator Protein Levels in Postmortem Human Alzheimer's Disease Brain.

Increased monoamine oxidase-A (MAO-A) activity in Alzheimer's disease (AD) may be detrimental to the point of neurodegeneration. To assess MAO-A activity in AD, we compared four biomarkers, Aβ plaques, tau, translocator protein (TSPO), and MAO-A in postmortem AD. Radiotracers were [F]FAZIN3 for MAO-A, [F]flotaza and [I]IBETA for Aβ plaques, [I]IPPI for tau, and [F]FEPPA for TSPO imaging.

Measurement of Aβ Amyloid Plaques and Tau Protein in Postmortem Human Alzheimer's Disease Brain by Autoradiography Using [F]Flotaza, [I]IBETA, [I]IPPI and Immunohistochemistry Analysis Using QuPath.

High-resolution scans of immunohistochemical (IHC) stains of Alzheimer's disease (AD) brain slices and radioligand autoradiography both provide information about the distribution of Aβ plaques and Tau, the two common proteinopathies in AD. Accurate assessment of the amount and regional location of Aβ plaques and Tau is essential to understand the progression of AD pathology. Our goal was to develop a quantitative method for the analysis of IHC-autoradiography images.

Abnormal [ F]NIFENE binding in transgenic 5xFAD mouse model of Alzheimer's disease: In vivo PET/CT imaging studies of α4β2* nicotinic acetylcholinergic receptors and in vitro correlations with Aβ plaques.

Since cholinergic dysfunction has been implicated in Alzheimer's disease (AD), the effects of Aβ plaques on nicotinic acetylcholine receptors (nAChRs) α4β2* subtype were studied using the transgenic 5xFAD mouse model of AD. Using the PET radiotracer [ F]nifene for α4β2* nAChRs, in vitro autoradiography and in vivo PET/CT studies in 5xFAD mice were carried out and compared with wild-type (C57BL/6) mice. Ratios of [ F]nifene binding in brain regions versus cerebellum (CB) in 5xFAD mice brains were for thalamus (TH) = 17, hippocampus-subiculum = 7, frontal cortex (FC) = 5.

Development of [I]IAZA as a New Proteinopathy Imaging Agent for Alzheimer's Disease.

Radioiodinated imaging agents for Aβ amyloid plaque imaging in Alzheimer’s disease (AD) patients have not been actively pursued. Our previous studies employed the “diaza” derivatives [11C]TAZA and [18F]flotaza in order to develop successful positron emission tomography (PET) imaging agents for Aβ plaques. There is a need for radioiodinated imaging agents for Aβ plaques for single photon emission computed tomography (SPECT) and PET imaging.

Elevated Monoamine Oxidase-A in Anterior Cingulate of Post-Mortem Human Parkinson's Disease: A Potential Surrogate Biomarker for Lewy Bodies?

Lewy bodies (LB) play a neuropathological role in Parkinson's disease (PD). Our goal was to evaluate LB using anti-ubiquitin immunohistochemistry (UIHC) and find correlations with monoamine oxidase-A (MAO-A) using imaging agent, [F]FAZIN3. Human post-mortem anterior cingulate (AC) and corpus callosum (CC) from control subjects (CN), = 6; age 81-90 LB = 0 and PD, = 6, age 77-89, LB = III-IV were sectioned (10 μm slices).

Trapping of Nicotinic Acetylcholine Receptor Ligands Assayed by Cellular Studies and PET Imaging.

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in brain. Ligands, like varenicline, with high pK and high affinity for α4β2-type nicotinic receptors (α4β2Rs) are trapped in intracellular acidic vesicles containing α4β2Rs Nicotine, with lower pK and α4β2R affinity, is not trapped. Here, we extend our results by imaging nicotinic PET ligands in male and female mouse brain and identifying the trapping brain organelle as Golgi satellites (GSats).

[I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer's Disease.

Several fluorine-18-labeled PET β-amyloid (Aβ) plaque radiotracers for Alzheimer’s disease (AD) are in clinical use. However, no radioiodinated imaging agent for Aβ plaques has been successfully moved forward for either single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Radioiodinated pyridyl benzofuran derivatives for the SPECT imaging of Aβ plaques using iodine-123 and iodine-125 are being pursued.

Four-modality imaging of unmedicated subjects with schizophrenia: F-fluorodeoxyglucose and F-fallypride PET, diffusion tensor imaging, and MRI.

Diminished prefrontal function, dopaminergic abnormalities in the striatum and thalamus, reductions in white matter integrity and frontotemporal gray matter deficits are the most replicated findings in schizophrenia. We used four imaging modalities (F-fluorodeoxyglucose and F-fallypride PET, diffusion tensor imaging, structural MRI) in 19 healthy and 25 schizophrenia subjects to assess the relationship between functional (dopamine D/D receptor binding potential, glucose metabolic rate) and structural (fractional anisotropy, MRI) correlates of schizophrenia and their additive diagnostic prediction potential. Multivariate ANOVA was used to compare structural and functional image sets for identification of schizophrenia.

[F]Nifene PET/CT Imaging in Mice: Improved Methods and Preliminary Studies of α4β2* Nicotinic Acetylcholinergic Receptors in Transgenic A53T Mouse Model of α-Synucleinopathy and Post-Mortem Human Parkinson's Disease.

We report [F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson's disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies.

Reading abilities and dopamine D/D receptor availability: An inverted U-shaped association in subjects with schizophrenia.

Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects' scores were positively and linearly associated with D/D receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous.

[ F]FDG PET/CT Studies in Transgenic Hualpha-Syn (A53T) Parkinson's Disease Mouse Model of α-Synucleinopathy.

Transgenic mice line M83 that express the A53T mutant α-synuclein protein at six times the level of endogenous mice α-synuclein are a model of α-synucleinopathy found in Parkinson's disease (PD). This Hualpha-Syn (A53T) PD model is useful in assessing non-motor deficits at earlier stages of onset of PD. We report findings on metabolic changes using [F]FDG PET/CT in the Hualpha-Syn (A53T) PD mouse model in comparison to non-carrier mice.

Development and evaluation of [F]Flotaza for Aβ plaque imaging in postmortem human Alzheimer's disease brain.

Positron emission tomographic (PET) studies of amyloid β (Aβ) accumulation in Alzheimer's disease (AD) have shown clinical utility. The aim of this study was to develop and evaluate the effectiveness of a new fluorine-18 radiotracer [F]Flotaza (2-{2-[2-[F]fluoroethoxy]ethoxy}ethoxy)-4'-N,N-dimethylaminoazobenzene), for Aβ plaque imaging. Nucleophilic [F]fluoride was used in a one-step radiosynthesis for [F]flotaza.

Development and evaluation of [ I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain.

Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6-[ I]iodo-3-(1H-pyrrolo[2,3-c]pyridine-1-yl)isoquinoline ([ I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN).

Development of zirconium-89 PET for imaging of alpha-klotho.

Alpha-klotho is a single-pass membrane protein primarily expressed by the kidneys. Klotho deficiency in chronic kidney disease contributes to an accelerated aging phenotype. We report here development of [Zr]DFO-anti-klotho positron emission tomography (PET) imaging as a novel non-invasive method for assessing whole-body alpha-klotho distribution.

Positive association between cerebral grey matter metabolism and dopamine D/D receptor availability in healthy and schizophrenia subjects: An F-fluorodeoxyglucose and F-fallypride positron emission tomography study.

Overlapping decreases in extrastriatal dopamine D/D-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental. To ascertain this, we used two consecutive F-fluorodeoxyglucose and F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects.

Dopamine receptor density and white mater integrity: F-fallypride positron emission tomography and diffusion tensor imaging study in healthy and schizophrenia subjects.

Dopaminergic dysfunction and changes in white matter integrity are among the most replicated findings in schizophrenia. A modulating role of dopamine in myelin formation has been proposed in animal models and healthy human brain, but has not yet been systematically explored in schizophrenia. We used diffusion tensor imaging and F-fallypride positron emission tomography in 19 healthy and 25 schizophrenia subjects to assess the relationship between gray matter dopamine D/D receptor density and white matter fractional anisotropy in each diagnostic group.

Dual targeting agents for Aβ plaque/P-glycoprotein and Aβ plaque/nicotinic acetylcholine α4β2* receptors-potential approaches to facilitate Aβ plaque removal in Alzheimer's disease brain.

Alzheimer's disease (AD) affects 10% of people older than 65 and is characterized by a progressive loss of cognitive function with an abnormal accumulation of amyloid β (Aβ ) plaques and neurofibrillary tangles (NFT) in the brain. Efforts to reduce brain Aβ plaques continue to be investigated as a therapeutic approach for AD. We report here development of dual targeting agents with affinity for Aβ plaque/P-glycoprotein (Pgp) and Aβ plaque/α4β 2* nicotinic acetylcholine receptors (nAChR).