Difluoromethoxide Is a Strong Leaving Group in the Photoredox Deoxyradiofluorination of 2-Phenylpyridines.

A 2-phenyl-3-difluoromethoxy-pyridinyl moiety features in potent phosphodiesterase 4D inhibitors that are considered to be candidate radiotracers for positron emission tomography if they are labeled with fluorine-18. Fluorine-18 could be installed as desired at the 3'-phenyl position with acridinium-mediated photoredox radiodeoxyfluorination in homologues bearing variously substituted 3'-aryloxy groups. However, a distal 3-difluoromethoxide (-OCHF) group strongly competes as a leaving group, especially when an electron-deficient aryloxy group is present at position 3'.

Gas Phase Transformations in Carbon-11 Chemistry.

The short-lived positron-emitter carbon-11 ( = 20.4 min; β, 99.8%) is prominent for labeling tracers for use in biomedical research with positron emission tomography (PET).

On the Risk of F-Regioisomer Formation in the Copper-Free Radiofluorination of Aryliodonium Precursors.

Aryliodonium precursors are widely applied for copper-free labeling of positron emission tomography (PET) tracers with fluorine-18. We assessed F-fluoroarene regioisomer formation in examples of these labeling methods. Aryliodonium ylides derived from Meldrum's acid bearing electron-donating groups react with [F]fluoride in acetonitrile to produce regioisomeric F-fluoroarenes via a competing aryne pathway.

An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands.

A positron emission tomography (PET) radioligand for imaging phosphodiesterase 4D (PDE4D) would benefit drug discovery and the investigation of neuropsychiatric disorders. The most promising radioligand to date, namely, [C]T1650, has shown unstable quantification in humans. Structural elaboration of [C]T1650 was therefore deemed necessary.

Broad Scope and High-Yield Access to Unsymmetrical Acyclic [ C]Ureas for Biomedical Imaging from [ C]Carbonyl Difluoride.

Effective methods are needed for labelling acyclic ureas with carbon-11 (t =20.4 min) as potential radiotracers for biomedical imaging with positron emission tomography (PET). Herein, we describe the rapid and high-yield syntheses of unsymmetrical acyclic [ C]ureas under mild conditions (room temperature and within 7 min) using no-carrier-added [ C]carbonyl difluoride with aliphatic and aryl amines.

PET ligands [F]LSN3316612 and [C]LSN3316612 quantify -linked-β--acetyl-glucosamine hydrolase in the brain.

We aimed to develop effective radioligands for quantifying brain -linked-β--acetyl-glucosamine (-GlcNAc) hydrolase (OGA) using positron emission tomography in living subjects as tools for evaluating drug target engagement. Posttranslational modifications of tau, a biomarker of Alzheimer's disease, by -GlcNAc through the enzyme pair OGA and -GlcNAc transferase (OGT) are inversely related to the amounts of its insoluble hyperphosphorylated form. Increase in tau -GlcNAcylation by OGA inhibition is believed to reduce tau aggregation.

[ C]Carbonyl Difluoride-a New and Highly Efficient [ C]Carbonyl Group Transfer Agent.

Herein, the synthesis and use of [ C]carbonyl difluoride for labeling heterocycles with [ C]carbonyl groups in high molar activity is described. A very mild single-pass gas-phase conversion of [ C]carbon monoxide into [ C]carbonyl difluoride over silver(II) fluoride provides easy access to this new synthon in robust quantitative yield for labeling a broad range of cyclic substrates, for example, imidazolidin-2-ones, thiazolidin-2-ones, and oxazolidin-2-ones. Labeling reactions may utilize close-to-stoichiometric precursor quantities and short reaction times at room temperature in a wide range of solvents while also showing high water tolerability.

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]-(4-(4-(3-Chloro-2-methoxyphenyl)-piperazin-1-yl)butyl)-1-indole-2-carboxamide ([C]BAK4-51) Is an Efflux Transporter Substrate and Ineffective for PET Imaging of Brain D₃ Receptors in Rodents and Monkey.

Selective high-affinity antagonists for the dopamine D₃ receptor (D₃R) are sought for treating substance use disorders. Positron emission tomography (PET) with an effective D₃R radioligand could be a useful tool for the development of such therapeutics by elucidating pharmacological specificity and target engagement in vivo. Currently, a D₃R-selective radioligand does not exist.

Quinuclidine and DABCO Enhance the Radiofluorinations of 5-Substituted 2-Halopyridines.

Positron emission tomography (PET) is an important molecular imaging technique for medical diagnosis, biomedical research and drug development. PET tracers for molecular imaging contain β-emitting radionuclides, such as carbon-11 ( = 20.4 min) or fluorine-18 ( = 109.

[Carboxyl- C]Labelling of Four High-Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography.

Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high-affinity (IC 2.

Pd(0)-Mediated C-Carbonylation of Aryl(mesityl)iodonium Salts as a Route to [C]Arylcarboxylic Acids and Derivatives.

Pd(0)-mediated C-carbonylation of aryl(mesityl)iodonium salts followed by suitable quench provides a rapid room-temperature two-pot procedure for labeling arylcarboxylic acids and amide derivatives with the short-lived positron emitter carbon-11 (t = 20.4 min) in generally good to high yields (up to 71%). High product ring selectivity (≥13) was achieved when using mesityl as a spectator group in the diaryliodonium salt precursors.

C-Labeling of Aryl Ketones as Candidate Histamine Subtype-3 Receptor PET Radioligands through Pd(0)-Mediated C-Carbonylative Coupling.

Pd(0)-mediated coupling between iodoarenes, [C]carbon monoxide and aryltributylstannanes has been used to prepare simple model [C]aryl ketones. Here, we aimed to label four 2-aminoethylbenzofuran chemotype based molecules ([C]-) in the carbonyl position, as prospective positron emission tomography (PET) radioligands for the histamine subtype 3 receptor (H3R) by adapting this methodology with use of aryltrimethylstannanes. Radiosynthesis was successfully performed on a platform equipped with a mini-autoclave and a liquid handling robotic arm, within a lead-shielded hot-cell.

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination.

New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group.

Exploration of the labeling of [11C]tubastatin A at the hydroxamic acid site with [11C]carbon monoxide.

We aimed to label tubastatin A (1) with carbon-11 (t1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one-pot Pd-mediated insertion of [(11)C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [(11) C]1.

An Investigation of (Diacetoxyiodo)arenes as Precursors for Preparing No-Carrier-Added [(18)F]Fluoroarenes from Cyclotron-Produced [(18)F]Fluoride Ion.

Treatment of (diacetoxyiodo)arenes (1a-1u) with cyclotron-produced [(18)F]fluoride ion rapidly affords no-carrier-added [(18)F]fluoroarenes (2a-2u) in useful yields and constitutes a new method for converting substituted iodoarenes into substituted [(18)F]fluoroarenes in just two steps.

[carbonyl-11C]4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([11C]FIMX) is an effective radioligand for PET imaging of metabotropic glutamate receptor 1 (mGluR1) in monkey brain.

Introduction: Metabotropic glutamate subtype receptor 1 (mGluR1) is implicated in several neuropsychiatric disorders and is a target for drug development. [(18)F]FIMX ([(18)F]4-fluoro--N-methyl-N--(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide) is an effective radioligand for imaging brain mGluR1 with PET. A similarly effective radioligand with a shorter half-life would usefully allow PET studies of mGluR1 at baseline and after pharmacological or other challenge on the same day.

The Inhibitor Ko143 Is Not Specific for ABCG2.

Imaging ATP-binding cassette (ABC) transporter activity in vivo with positron emission tomography requires both a substrate and a transporter inhibitor. However, for ABCG2, there is no inhibitor proven to be specific to that transporter alone at the blood-brain barrier. Ko143 [[(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1',2':1,6]pyrido[3,4- b]indole-3-propanoic acid 1,1-dimethylethyl ester], a nontoxic analog of fungal toxin fumitremorgin C, is a potent inhibitor of ABCG2, although its specificity in mouse and human systems is unclear.

Enhanced Nucleophilic Fluorination and Radiofluorination of Organosilanes Appended with Potassium-Chelating Leaving Groups.

Here we aimed to explore the feasibility of enhancing the fluorination of organosilanes by appending potassium-chelating groups to the substrates. For this purpose, eight organosilanes were prepared in which a linear or cyclic leaving group, with putative potassium-chelating ability, was attached covalently to a congested silicon atom via an ether linkage to serve as a potential nucleophilic assisting leaving group (NALG). Organosilicon-NALGs with expected strong potassium-chelating capability enhanced reactions with potassium fluoride in acetonitrile to produce organofluorosilanes without any need to separately add phase transfer reagent.

(11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to α(1) adrenoceptors in brain.

Unlabelled: The PET radioligand (11)C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.

Radiofluorination of diaryliodonium tosylates under aqueous-organic and cryptand-free conditions.

Positron emission tomography (PET) has growing importance as a molecular imaging technique in clinical research and drug development. Methods for producing PET radiotracers utilizing cyclotron-produced [(18)F]fluoride ion (t1/2 = 109.7 min) without the need for complete removal of irradiated target [(18)O]water and addition of cryptand are keenly sought for practical convenience and efficiency.

[¹¹C]Rhodamine-123: synthesis and biodistribution in rodents.

Introduction: Rhodamine-123 is a known substrate for the efflux transporter, P-glycoprotein (P-gp). We wished to assess whether rhodamine-123 might serve as a useful substrate for developing probes for imaging efflux transporters in vivo with positron emission tomography (PET). For this purpose, we aimed to label rhodamine-123 with carbon-11 (t(1/2)=20.

Radiosynthesis and evaluation of an (18)F-labeled positron emission tomography (PET) radioligand for brain histamine subtype-3 receptors based on a nonimidazole 2-aminoethylbenzofuran chemotype.

A known chemotype of H(3) receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H(3)) receptors in vivo with positron emission tomography (PET), namely nonimidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t(1/2) = 109.7 min) in high specific activity by treating the prepared nitro analogue (12) with cyclotron-produced [(18)F]fluoride ion.

Cu(I)-catalyzed (11)C carboxylation of boronic acid esters: a rapid and convenient entry to (11)C-labeled carboxylic acids, esters, and amides.

Rapid and direct: the carboxylation of boronic acid esters with (11)CO(2) provides [(11)C]carboxylic acids as a convenient entry into [(11)C]esters and [(11)C]amides. This conversion of boronates is tolerant to diverse functional groups (e.g.