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This report describes a copper-mediated radiocyanation of aryl halides that is applicable to complex molecules. This transformation tolerates an exceptionally wide range of functional groups, including unprotected amino acids. As such, it enables the site-specific introduction of (11)C[CN] into peptides at an iodophenylalanine residue. The use of a diamine-ligated copper(I) mediator is crucial for achieving high radiochemical yield under relatively mild conditions, thus limiting racemization and competing side reactions of other amino acid side chains. The reaction has been scaled and automated to deliver radiolabeled peptides, including analogues of adrenocorticotropic hormone 1–27 (ACTH) and nociceptin (NOP). For instance, this Cu-mediated radiocyanation was leveraged to prepare >40 mCi of [(11)C]cyano-NOP to evaluate biodistribution in a primate using positron emission tomography. This investigation provides preliminary evidence that nociceptin crosses the blood-brain barrier and shows uptake across all brain regions (SUV >1 at 60 min post-injection), consistent with the known distribution of NOP receptors in the rhesus brain.

This article describes a sequential Ir/Cu-mediated process for the meta-selective C-H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp2)-H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [18F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a benchtop without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FXFN module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [18F]1-fluoro-3,5-dimethoxybenzene and an 18F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (Am), respectively.

PURPOSE: Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C-(18)F bonds. This minireview examines proof-of-concept, pre-clinical, and in-human imaging studies of new and established imaging agents containing aromatic C-(18)F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed. METHODS: A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion. CONCLUSIONS: CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.

Positron emission tomography (PET) is an important non-invasive tool to help guide the drug discovery and development process. Positron-emitting–radiolabeled drug candidates represent an important tool for drug hunters to gain insight into a drug's biodistribution and target engagement of exploratory biologic targets of interest. Recently, there have been several drug candidates that incorporate an acryloyl functional group due to their ability to form a covalent bond within the biological target of interest through Michael addition. Methods to incorporate a carbon-11 radionuclide into acrylamide derivatives remain challenging given the reactive nature of this moiety. Herein, we report the improved radiosynthesis of carbon-11–containing acrylamide drug candidates, [11C]ibrutinib, [11C]tolebrutinib, and [11C]evobrutinib, using [11C]CO and a novel “in-loop” 11C-carbonylation reaction. [11C]Ibrutinib, [11C]tolebrutinib, and [11C]evobrutinib were reliably synthesized, generating 2.2-7.1 GBq of these radiopharmaceuticals in radiochemical yields ranging from 3.3 to 12.8% (non-decay corrected; relative to starting [11C]CO2) and molar activities of 281-500 GBq/μmol (7.5-13.5 Ci/μmol), respectively. This study highlights an improved method for incorporating carbon-11 into acrylamide drug candidates using [11C]CO within an HPLC loop suitable for clinical translation using simple modifications of standard automated synthesis modules used for cGMP manufacture of PET radioligands.

This Article describes a sequential Ir/Cu-mediated process for the meta-selective C─H radiofluorination of (hetero)arene substrates. In the first step, Ir-catalyzed C(sp(2))─H borylation affords (hetero)aryl pinacolboronate (BPin) esters. The intermediate organoboronates are then directly subjected to copper-mediated radiofluorination with [(18)F]tetrabutylammonium fluoride to afford fluorine-18 labeled (hetero)arenes in high radiochemical yield and radiochemical purity. This entire process is performed on a bench-top without Schlenk or glovebox techniques and circumvents the need to isolate (hetero)aryl boronate esters. The reaction was automated on a TracerLab FX(FN) module with 1,3-dimethoxybenzene and a meta-tyrosine derivative. The products, [(18)F]1-fluoro-3,5-dimethoxybenzene and an (18)F-labeled meta-tyrosine derivative, were obtained in 37 ± 5% isolated radiochemical yield and >99% radiochemical purity and 25% isolated radiochemical yield and 99% radiochemical purity, and 0.52 Ci/μmol (19.24 GBq/μmol) molar activity (A(m)), respectively.

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Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g., 18F). In recent years, new reactions have appeared for the 18F-labeling of agents that are difficult to access by applying traditional radiochemistry, for example those requiring 18F incorporation into unactivated (hetero)arenes. However, automation of these new methods for translation to the clinic has progressed slowly because extensive modification of manual protocols is typically required when implementing novel 18F-labeling methodologies within automated modules. Here, we describe the workflow that led to the automated radiosynthesis of the poly(ADP-ribose) polymerase (PARP) inhibitor [18F]olaparib. First, we established a robust manual protocol to prepare [18F]olaparib from the protected N-[2-(trimethylsilyl)ethoxy]methyl (SEM) arylboronate ester precursor in a 17% ± 5% (n = 15; synthesis time, 135 min) non-decay-corrected (NDC) activity yield, with molar activity (Am) up to 34.6 GBq/µmol. Automation of the process, consisting of copper-mediated 18F-fluorodeboronation followed by deprotection, was achieved on an Eckert & Ziegler Modular-Lab radiosynthesis platform, affording [18F]olaparib in a 6% ± 5% (n = 3; synthesis time, 120 min) NDC activity yield with Am up to 319 GBq/µmol. Automation of new methods for 18F incorporation into unactivated (hetero)arenes for translation to the clinic has progressed slowly. This protocol describes a workflow leading to automated radiosynthesis of the PARP inhibitor [18F]olaparib.

Molecules labeled with fluorine-18 ((18)F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of (18)F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated (18)F-fluorination of aryl boron reagents with (18)F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of (18)F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.

Positron emission tomography (PET) is a diagnostic nuclear imaging modality that relies on automated protocols to prepare agents labeled with a positron-emitting radionuclide (e.g.

In this work, we describe the (18)F-labeling of α,α-difluoro-α-(aryloxy)acetic acid derivatives and demonstrate that these building blocks are amenable to post-(18)F-fluorination functionalization. Protodecarboxylation offers a new entry to (18)F-difluoromethoxyarene, and the value of this approach is further demonstrated with coupling processes leading to representative (18)F-labeled TRPV1 inhibitors and TRPV1 antagonists.

Molecules labeled with fluorine-18 (

In this work, we describe the

A general method for the copper mediated nucleophilic

International audience; [18F]FMTEB, [18F]FPEB, [18F]flumazenil, [18F]DAA1106, [18F]MFBG, [18F]FDOPA, [18F]FMT and [18F]FDA are prepared from the corresponding arylboronic esters and [18F]KF/K222 in the presence of Cu(OTf)2py4. The method was successfully applied using three radiosynthetic platforms, and up to 26 GBq of non-carrier added starting activity of 18F-fluoride.

Molecules labeled with fluorine-18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (SNAr) with [ 18F]F-. In the ideal case, the 18F fluorination of these substrates would be performed through reaction of [18F]KF with shelf-stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of 18F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [18F]KF/K 222 and [Cu(OTf)2(py)4] (OTf= trifluoromethanesulfonate, py=pyridine). This method tolerates electron-poor and electron-rich arenes and various functional groups, and allows access to 6-[18F]fluoro-L-DOPA, 6-[18F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [18F]DAA1106. 18F-labeling for PET: The nucleophilic 18F fluorination of pinacol-derived aryl boronic esters is achieved with [18F]KF/K 222 in the presence of [Cu(OTf)2(py)4] (OTf=trifluoromethanesulfonate, py=pyridine); this unprecedented method can produce a clinical dose of 6-[18F]fluoro-L-DOPA in two steps (fluorination followed by deprotection) from a readily available shelf-stable arylBPin precursor (see scheme). RCY=decay-corrected radiochemical yield © 2014 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim.