Head-to-head comparison of [F]-Flortaucipir, [F]-MK-6240 and [F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases.

We and others have shown that [F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [F]-MK-6240 and [F]-PI-2620 are the two that have garnered most attention.

PET imaging studies to investigate functional expression of mGluR2 using [C]mG2P001.

Metabotropic glutamate receptor 2 (mGluR2) has been extensively studied for the treatment of various neurological and psychiatric disorders. Understanding of the mGluR2 function is pivotal in supporting the drug discovery targeting mGluR2. Herein, the positive allosteric modulation of mGluR2 was investigated via the positron emission tomography (PET) imaging using 2-((4-(2-[C]methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1-imidazo[4,5-]pyridine ([C]mG2P001).

Radiosynthesis and evaluation of [C]AG-488, a dual anti-angiogenetic and anti-tubulin PET ligand.

Combinations of antiangiogenic and cytotoxic agents show promising results in the treatment of cancer. However, there is a lack of single agent with both antiangiogenic and cytotoxic activities for clinical application. AG-488 aka FLAG-003 is a novel ligand with established antiangiogenetic properties via activation of receptor thymidine kinase (RTK) and anti-tubulin properties in tumor cells.

In vivo imaging of mGlu5 receptor expression in humans with Fragile X Syndrome towards development of a potential biomarker.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by silencing of the Fragile X Mental Retardation (FMR1) gene. The resulting loss of Fragile X Mental Retardation Protein (FMRP) leads to excessive glutamate signaling via metabotropic glutamate subtype 5 receptors (mGluR5) which has been implicated in the pathogenesis of the disorder. In the present study we used the radioligand 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([F]FPEB) in simultaneous PET-MR imaging of males with FXS and age- and gender-matched controls to assess the availability of mGlu5 receptors in relevant brain areas.

Radiochemical Synthesis and Evaluation in Non-Human Primates of 3-[C]methoxy-4-aminopyridine: A Novel PET Tracer for Imaging Potassium Channels in the CNS.

Demyelination, the loss of the protecting sheath of neurons, contributes to disability in many neurological diseases. In order to fully understand its role in different diseases and to monitor treatments aiming at reversing this process, it would be valuable to have PET radiotracers that can detect and quantify molecular changes involved in demyelination such as the uncovering and upregulation of the axonal potassium channels K1.1 and K1.

Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2.

Three benzimidazole derivatives (-) have been synthetized as potential positron emission tomography (PET) imaging ligands for mGluR2 in the brain. Of these compounds, exhibits potent binding affinity (IC = 7.6 ± 0.

Development, validation and regulatory acceptance of improved purification and simplified quality control of [N] Ammonia.

Background: [N]Ammonia is a cyclotron produced myocardial perfusion imaging agent. With the development of high-yielding [N]ammonia cyclotron targets using a solution of 5 mM ethanol in water, there was a need to develop and validate an automated purification and formulation system for [N]ammonia to be in a physiological compatible formulation of 0.9% sodium chloride since there is no widely available commercial system at this time.

Novel radioligands for imaging sigma-1 receptor in brain using positron emission tomography (PET).

The sigma-1 receptor ( R) is a unique intracellular protein. R plays a major role in various pathological conditions in the central nervous system (CNS), implicated in several neuropsychiatric disorders. Imaging of R in the brain using positron emission tomography (PET) could serve as a noninvasively tool for enhancing the understanding of the disease's pathophysiology.

Radiosynthesis and preclinical evaluation of [ C]Cimbi-701 - Towards the imaging of cerebral 5-HT receptors.

The serotonin 7 (5-HT ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer.

Autoradiography validation of novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue.

[F-18]-MK-6240, a novel tau positron emission tomography (PET) tracer recently discovered for the in vivo detection of neurofibrillary tangles, has the potential to improve diagnostic accuracy in the detection of Alzheimer disease. We have examined regional and substrate-specific binding patterns as well as possible off-target binding of this tracer on human brain tissue to advance towards its validation. We applied [F-18]-MK-6240 phosphor screen and high resolution autoradiography to postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration-tau (Pick's disease, progressive supranuclear palsy and corticobasal degeneration), chronic traumatic encephalopathy, frontotemporal lobar degeneration-Tar DNA-binding protein 43 (TDP-43), dementia with Lewy bodies, cerebral amyloid angiopathy and elderly controls free of pathologic changes of neurodegenerative disease.

Interaction of azadirachtin with the lipid-binding domain: Suppression of lipid transportation in the silkworm, Bombyx mori.

This study investigates the effects of the insect growth regulator azadirachtin on lipid transportation to the ovary of the silkworm, Bombyx mori. Lipids are hydrophobic in nature and require a carrier for circulation in the blood. Protein-lipid interactions play a vital role in lipid transport, thereby keeping the system balanced.

Discrepancies in Kappa Opioid Agonist Binding Revealed through PET Imaging.

Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression, and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BP, binding potential with respect to non-displaceable uptake).

[F]Fluorocholine and [F]Fluoroacetate PET as Imaging Biomarkers to Assess Phosphatidylcholine and Mitochondrial Metabolism in Preclinical Models of TSC and LAM.

Purpose: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations of the or gene, characterized by neurocognitive impairment and benign tumors of the brain, skin, heart, and kidneys. Lymphangioleiomyomatosis (LAM) is a diffuse proliferation of α-smooth muscle actin-positive cells associated with cystic destruction of the lung. LAM occurs almost exclusively in women, as a TSC manifestation or a sporadic disorder ( somatic mutations).

Association of Angiotensin-Converting Enzyme Gene Polymorphisms and Nephropathy in Diabetic Patients at a Tertiary Care Centre in South India.

Background: Genetic polymorphisms of the angiotensin-renin pathway have been thought to influence the development of diabetic nephropathy. However, there are conflicting results regarding this association in previous studies on populations with varying ethnicity.

Aims: Primary aim was to compare the frequency of distribution of angiotensin-converting enzyme () gene (insertion/deletion [I/D]) polymorphism in Tamilian Indian type 2 diabetic individuals with and without microalbuminuria.

cGMP production of the radiopharmaceutical [ F]MK-6240 for PET imaging of human neurofibrillary tangles.

Fluorine-18-labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ F]MK-6240) is a novel potent and selective positron emission tomography (PET) radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated 2-step radiosynthesis of [ F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare TRACERlab FX . Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [ F]fluoride (K[ F]/K ) was performed by conventional heating, followed by acid deprotection and semipreparative high-performance liquid chromatography under isocratic conditions.

A report of the automated radiosynthesis of the tau positron emission tomography radiopharmaceutical, [ F]-THK-5351.

The radiotracer, [ F]-THK-5351, is a highly selective and high-binding affinity PET imaging agent for aggregates of hyper-phosphorylated tau protein. Our report is a simplified 1-pot, 2-step radiosynthesis of [ F]-THK-5351. This report is broadly applicable for routine clinical production and multi-center trials on account of favorable half-life of flourine-18 and the use of a commercially available radiosynthesis module, the GE TRACERlab™ FX .

Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance.

Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [(11)C]Martinostat, has enabled the study of histone deacetylase in living human subjects.

Instability of viscous flow over a deformable two-layered gel: experiments and theory.

The instability of the flow of a viscous fluid past a soft, two-layered gel is probed using experiments, and the observations are compared with results from a linear stability analysis. The experimental system consists of the rotating top plate of a rheometer and its stationary bottom plate on which the two-layer gel is placed. When the flow between the top plate and the two-layer gel is viscometric (i.

PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat.

Histone deacetylase (HDAC) enzymes have been demonstrated as critical components in maintaining chromatin homeostasis, CNS development, and normal brain function. Evidence in mouse models links HDAC expression to learning, memory, and mood-related behaviors; small molecule HDAC inhibitor tool compounds have been used to demonstrate the importance of specific HDAC subtypes in modulating CNS-disease-related behaviors in rodents. So far, no direct evidence exists to understand the quantitative changes in HDAC target engagement that are necessary to alter biochemistry and behavior in a living animal.

Synthesis and imaging validation of [¹⁸F]MDL100907 enabled by Ni-mediated fluorination.

Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT2a imaging using innovative chemistry.

Late stage benzylic C-H fluorination with [¹⁸F]fluoride for PET imaging.

We describe the first late-stage (18)F labeling chemistry for aliphatic C-H bonds with no-carrier-added [(18)F]fluoride. The method uses Mn(salen)OTs as an F-transfer catalyst and enables the facile labeling of a variety of bioactive molecules and building blocks with radiochemical yields (RCY) ranging from 20% to 72% within 10 min without the need for preactivation of the labeling precursor. Notably, the catalyst itself can directly elute [(18)F]fluoride from an ion exchange cartridge with over 90% efficiency.

Imaging evaluation of 5HT2C agonists, [(11)C]WAY-163909 and [(11)C]vabicaserin, formed by Pictet-Spengler cyclization.

The serotonin subtype 2C (5HT2C) receptor is an emerging and promising drug target to treat several disorders of the human central nervous system. In this current report, two potent and selective 5HT2C full agonists, WAY-163909 (2) and vabicaserin (3), were radiolabeled with carbon-11 via Pictet-Spengler cyclization with [(11)C]formaldehyde and used in positron emission tomography (PET) imaging. Reaction conditions were optimized to exclude the major source of isotope dilution caused by the previously unknown breakdown of N,N-dimethylformamide (DMF) to formaldehyde at high temperature under mildly acid conditions.

Design, synthesis, and evaluation of hydroxamic acid-based molecular probes for in vivo imaging of histone deacetylase (HDAC) in brain.

Hydroxamic acid-based histone deacetylase inhibitors (HDACis) are a class of molecules with therapeutic potential currently reflected in the use of suberoylanilide hydroxamic acid (SAHA; Vorinostat) to treat cutaneous T-cell lymphomas (CTCL). HDACis may have utility beyond cancer therapy, as preclinical studies have ascribed HDAC inhibition as beneficial in areas such as heart disease, diabetes, depression, neurodegeneration, and other disorders of the central nervous system (CNS). However, little is known about the pharmacokinetics (PK) of hydroxamates, particularly with respect to CNS-penetration, distribution, and retention.

Radiosynthesis and evaluation of [11C]EMPA as a potential PET tracer for orexin 2 receptors.

EMPA is a selective antagonist of orexin 2 (OX2) receptors. Previous literature with [(3)H]-EMPA suggest that it may be used as an imaging agent for OX2 receptors; however, brain penetration is known to be modest. To evaluate the potential of EMPA as a PET radiotracer in non-human primate (as a step to imaging in man), we radiolabeled EMPA with carbon-11.