Derisking the Cu-mediated (18)F-fluorination of heterocyclic positron emission tomography radioligands

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

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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

A general copper-mediated nucleophilic 18F fluorination of arenes.

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 [(18)F]F(-). In the ideal case, the (18)F fluorination of these substrates would be performed through reaction of [(18)F]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 (18)F arenes from pinacol-derived aryl boronic esters (arylBPin) upon treatment with [(18)F]KF/K222 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-[(18)F]fluoro-L-DOPA, 6-[(18)F]fluoro-m-tyrosine, and the translocator protein (TSPO) PET ligand [(18)F]DAA1106

A general copper-mediated nucleophilic 18F fluorination of arenes

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