Ligand-based design of [F]OXD-2314 for PET imaging in non-Alzheimer's disease tauopathies.

Positron emission tomography (PET) imaging of tau aggregation in Alzheimer's disease (AD) is helping to map and quantify the in vivo progression of AD pathology. To date, no high-affinity tau-PET radiopharmaceutical has been optimized for imaging non-AD tauopathies. Here we show the properties of analogues of a first-in-class 4R-tau lead, [F]OXD-2115, using ligand-based design.

C-Fixation Techniques.

This protocol describes the application of cyclotron-generated [C]CO fixation reactions for direct C-carboxylation reactions and [C]CO for C-carbonylations. Herein we describe one-pot methods wherein the radioactive gas is first trapped in a reaction mixture at room temperature and atmospheric pressure prior to the radiolabeling reactions. Such procedures are widely applicable to numerous small molecules to form C-labeled carboxylic acids, amides, esters, ketones, oxazolidinones, carbamates, and ureas.

First-in-Human PET Imaging of [F]SDM-4MP3: A Cautionary Tale.

[F]SynVesT-1 is a PET radiopharmaceutical that binds to the synaptic vesicle protein 2A (SV2A) and serves as a biomarker of synaptic density with widespread clinical research applications in psychiatry and neurodegeneration. The initial goal of this study was to concurrently conduct PET imaging studies with [F]SynVesT-1 at our laboratories. However, the data in the first two human PET studies had anomalous biodistribution despite the injected product meeting all specifications during the prerelease quality control protocols.

Preliminary PET imaging of [C]evobrutinib in mouse models of colorectal cancer, SARS-CoV-2, and lung damage: Radiosynthesis via base-aided palladium-NiXantphos-mediated C-carbonylation.

Evobrutinib is a second-generation, highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in the autoimmune diseases arthritis and multiple sclerosis. Its development as a positron emission tomography (PET) radiotracer has potential for in vivo imaging of BTK in various disease models including several cancers, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), and lipopolysaccharide (LPS)-induced lung damage. Herein, we report the automated radiosynthesis of [C]evobrutinib using a base-aided palladium-NiXantphos-mediated C-carbonylation reaction.

Reactive Palladium-Ligand Complexes for C-Carbonylation at Ambient Pressure: A Breakthrough in Carbon-11 Chemistry.

The Pd-Xantphos-mediated C-carbonylation protocol (also known as the "Xantphos- method"), due to its simplistic and convenient nature, has facilitated researchers in meeting a longstanding need for preparing C-carbonyl-labeled radiopharmaceuticals at ambient pressure for positron emission tomography (PET) imaging and drug discovery. This development could be viewed as a breakthrough in carbon-11 chemistry, as evidenced by the rapid global adoption of the method by the pharmaceutical industry and academic laboratories worldwide. The method has been fully automated for the good manufacturing practice (GMP)-compliant production of novel radiopharmaceuticals for human use, and it has been adapted for "in-loop" reactions and microwave technology; an impressive number of C-labeled compounds (>100) have been synthesized.

Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers.

A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; ) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [H] provided (nM) values in AD = 4.0, PSP = 5.

Spirocyclic Iodonium Ylides for Fluorine-18 Radiolabeling of Non-Activated Arenes: From Concept to Clinical Research.

Positron emission tomography (PET) is a powerful imaging tool for drug discovery, clinical diagnosis, and monitoring of disease progression. Fluorine-18 is the most common radionuclide used for PET, but advances in radiotracer development have been limited by the historical lack of methodologies and precursors amenable to radiolabeling with fluorine-18. Radiolabeling of electron-rich (hetero)aromatic rings remains a long-standing challenge in the production of PET radiopharmaceuticals.

Strategies for designing novel positron emission tomography (PET) radiotracers to cross the blood-brain barrier.

Positron emission tomography (PET) is a powerful tool for imaging biological processes in the central nervous system (CNS). Designing PET radiotracers capable of crossing the blood-brain barrier (BBB) remains a major challenge. In addition to being brain-penetrant, a quantifiable CNS PET radiotracer must have high target affinity and selectivity, appropriate pharmacokinetics, minimal non-specific binding, negligible radiometabolites in the brain, and generally must be amenable to labeling with carbon-11 ( C) or fluorine-18 ( F).

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies.

Positron emission tomography (PET) is a molecular imaging technique that makes use of radiolabelled molecules for in vivo evaluation. Carbon-11 is a frequently used radionuclide for the labelling of small molecule PET tracers and can be incorporated into organic molecules without changing their physicochemical properties. While the short half-life of carbon-11 (C; t = 20.

Ring-opening of non-activated aziridines with [C]CO novel ionic liquids.

Novel ionic liquids based on DBU and DBN halide salts were developed as a catalytic system for ring-opening of non-activated aziridines with [C]CO. The ability of ionic liquids to activate aziridines represents a simple methodology for the synthesis of C-carbamates and can be extended for CO-fixation in organic and radiochemistry.

Radiosynthesis of [C]Ibrutinib Pd-Mediated [C]CO Carbonylation: Preliminary PET Imaging in Experimental Autoimmune Encephalomyelitis Mice.

Ibrutinib is a first-generation Bruton's tyrosine kinase (BTK) inhibitor that has shown efficacy in autoimmune diseases and has consequently been developed as a positron emission tomography (PET) radiotracer. Herein, we report the automated radiosynthesis of [C]ibrutinib through C-carbonylation of the acrylamide functional group, by reaction of the secondary amine precursor with [C]CO, iodoethylene, and palladium-NiXantphos. [C]Ibrutinib was reliably formulated in radiochemical yields of 5.

Preliminary Evaluations of [C]Verubulin: Implications for Microtubule Imaging With PET.

[C]Verubulin (a.k.a.

Radiosynthesis, and Evaluation of [F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies.

CBD-2115 was selected from a library of 148 compounds based on a pyridinyl-indole scaffold as a first-in-class 4R-tau radiotracer. In vitro binding assays showed [H]CBD-2115 had a value of 6.9 nM and a nominal of 500 nM in 4R-tau expressing P301L transgenic mouse tissue.

Potential for imaging the high-affinity state of the 5-HT receptor: a comparison of three PET radioligands with differing intrinsic activity.

Background: Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT receptors. The 5-HT receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand.

Development of a F-labeled PET radioligand for imaging 5-HT receptors: [F]AZ10419096.

Introduction: In the last decade PET has been useful in studying and understanding the 5-HT receptor. [C]AZ10419369 and [C]P943 have been applied as radioligands in these studies. Both use carbon-11 (t = 20.

Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT receptors.

Introduction: The serotonin 1B receptor subtype is of interest in the pathophysiology and treatment of depression, anxiety, and migraine. Over recent years 5-HT receptor binding in human brain has been examined with PET using radioligands that are partial but not full agonists. To explore how the intrinsic activity of a PET radioligand may affect imaging performance, two high-affinity full 5-HT receptor agonists (AZ11136118, 4; and AZ11895987, 5) were selected from a large compound library and radiolabeled for PET examination in non-human primates.

[C]AZ10419096 - a full antagonist PET radioligand for imaging brain 5-HT receptors.

Introduction: The serotonergic system is widely present in all regions of the central nervous system (CNS) and plays a key modulatory role in many of its functions. Positron emission tomography (PET) is used to study several serotonin receptors in CNS in vivo. The G-protein coupled receptor 5-HT is mostly present in the occipital cortex and in midbrain and is linked to several psychiatric disorders.