18F Labeling of Arenes

Molecular imaging has witnessed an upsurge in growth, with positron emission tomography leading the way. This trend has encouraged numerous synthetic chemists to enter the field of ¹⁸F‐radiochemistry and provide generic solutions to address the well‐recognized challenges of late‐stage fluorination. This Minireview focuses on recent developments in the ¹⁸F‐labeling of aromatic substrates.     

Chemistry for Positron Emission Tomography: Recent Advances in 11C‐, 18F‐, 13N‐, and 15O‐Labeling Reactions

Positron emission tomography (PET) is a molecular imaging technology that provides quantitative information about function and metabolism in biological processes in vivo for disease diagnosis and therapy assessment. The broad application and rapid advances of PET has led to an increased demand for new radiochemical methods to synthesize highly specific molecules bearing positron‐emitting radionuclides. This Review provides an overview of commonly used labeling reactions through examples of clinically relevant PET tracers and highlights the most recent developments and breakthroughs over the past decade, with a focus on ¹¹C, ¹⁸F, ¹³N, and ¹⁵O.     

One‐Pot,Direct Incorporation of [11C]CO2 into Carbamates

Why beat about the bush? An operationally simple and mild reaction based on the direct fixation of ¹¹CO₂ with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) has been developed for the synthesis of ¹¹C‐labeled carbamates at 75 °C within 10 minutes in radiochemical yields above 70 % (see scheme). This strategy should be immediately useful for the construction of new radiotracers for positron emission tomography and other applications.

     

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., halo, nitro, or carbonyl).     

One-Pot Synthesis of 11C-Labelled Primary Benzamides via Intermediate [11C]Aroyl Dimethylaminopyridinium Salts

Electrophilic ¹¹C-labelled aroyl dimethylaminopyridinium salts, obtained by carbonylative cross-coupling of aryl halides with [¹¹C]carbon monoxide, were prepared for the first time and shown to be valuable intermediates in the synthesis of primary [¹¹C]benzamides. The methodology furnished a set of benzamide model compounds, including the two poly (ADP-ribose) polymerase (PARP) inhibitors niraparib and veliparib, in moderate to excellent radiochemical yields. In addition to providing a convenient and practical route to primary [¹¹C]benzamides, the current method paves the way for future application of [¹¹C]aroyl dimethylaminopyridinium halide salts in positron emission tomography (PET) tracer synthesis.     

Broad Scope and High-Yield Access to Unsymmetrical Acyclic [11C]Ureas for Biomedical Imaging from [11C]Carbonyl Difluoride

Effective methods are needed for labelling acyclic ureas with carbon-11 (t_1/2=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 [¹¹C]ureas under mild conditions (room temperature and within 7 min) using no-carrier-added [¹¹C]carbonyl difluoride with aliphatic and aryl amines. This methodology is compatible with diverse functionality (e. g., hydroxy, carboxyl, amino, amido, or pyridyl) in the substrate amines. The labelling process proceeds through putative [¹¹C]carbamoyl fluorides and for primary amines through isolable [¹¹C]isocyanate intermediates. Unsymmetrical [¹¹C]ureas are produced with negligible amounts of unwanted symmetrical [¹¹C]urea byproducts. Moreover, the overall labelling method tolerates trace water and the generally moderate to excellent yields show good reproducibility. [¹¹C]Carbonyl difluoride shows exceptional promise for application to the synthesis of acyclic [¹¹C]ureas as new radiotracers for biomedical imaging with PET.     

Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography

Fluorine presents among its radioactive isotopes fluorine-18, that decays with a 109 min half-life and a β⁺ emission, allowing external detection of the two coincident γ photons obtained after annihilation. Production techniques (medical cyclotron), radiochemical reactions for isotope incorporation in radiopharmaceuticals and development of specific detection cameras (positron emission tomographs) allowed development of a vast investigation field in medical imaging.Applications of PET in oncology ([¹⁸F]fluorodeoxyglucose, FDG) largely improved detection and management of cancers; tracer molecules labelled with fluorine-18 also allow fruitful researches in molecular imaging.     

Organomediated Enantioselective 18F Fluorination for PET Applications

The first organomediated asymmetric ¹⁸F fluorination has been accomplished using a chiral imidazolidinone and [¹⁸F]N‐fluorobenzenesulfonimide. The method provides access to enantioenriched ¹⁸F‐labeled α‐fluoroaldehydes (>90 % ee), which are versatile chiral ¹⁸F synthons for the synthesis of radiotracers. The utility of this process is demonstrated with the synthesis of the PET (positron emission tomography) tracer (2S,4S)‐4‐[¹⁸F]fluoroglutamic acid.     

A Resin‐Linker‐Vector Approach to Radiopharmaceuticals Containing 18F: Application in the Synthesis of O‐(2‐[18F]‐Fluoroethyl)‐L‐tyrosine

A Resin‐linker‐vector (RLV) strategy is described for the radiosynthesis of tracer molecules containing the radionuclide ¹⁸F, which releases the labelled vector into solution upon nucleophilic substitution of a polystyrene‐bound arylsulfonate linker with [¹⁸F]‐fluoride ion. Three model linker‐vector molecules 7 a – c containing different alkyl spacer groups were assembled in solution from (4‐chlorosulfonylphenyl)alkanoate esters, exploiting a lipase‐catalysed chemoselective carboxylic ester hydrolysis in the presence of the sulfonate ester as a key step. The linker‐vector systems were attached to aminomethyl polystyrene resin through amide bond formation to give RLVs 8 a – c with acetate, butyrate and hexanoate spacers, which were characterised by using magic‐angle spinning (MAS) NMR spectroscopy. On fluoridolysis, the RLVs 8 a , b containing the longer spacers were shown to be more effective in the release of the fluorinated model vector (4‐fluorobutyl)phenylcarbamic acid tert‐butyl ester ( 9 ) in NMR kinetic studies and gave superior radiochemical yields (RCY≈60 %) of the ¹⁸F‐labelled vector. The approach was applied to the synthesis of the radiopharmaceutical O‐(2‐[¹⁸F]‐fluoroethyl)‐L ‐tyrosine ([¹⁸F]‐FET), delivering protected [¹⁸F]‐FET in >90 % RCY. Acid deprotection gave [¹⁸F]‐FET in an overall RCY of 41 % from the RLV.     

Purification of carbon-11 PET radiotracers from unlabeled precursors by preparative HPLC and SPE

A general methodology for the rapid purification of carbon-11 positron emission tomography (PET) radiotracers from radiolabeling reaction mixtures has been developed. Preparative HPLC and solid-phase extraction (SPE) techniques are described which can separate some commonly used radiopharmaceuticals such as [(11)C]raclopride, [(11)C]beta-CFT and [(11)C]choline from their unlabeled precursors.     

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 (S_NAr) 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/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‐[¹⁸F]fluoro‐L ‐DOPA, 6‐[¹⁸F]fluoro‐m‐tyrosine, and the translocator protein (TSPO) PET ligand [¹⁸F]DAA1106.     

Difluorocarbene‐Derived Trifluoromethylthiolation and [18F]Trifluoromethylthiolation of Aliphatic Electrophiles

The first trifluoromethylthiolation and [¹⁸F]trifluoromethylthiolation of alkyl electrophiles with in situ generated difluorocarbene in the presence of elemental sulfur and external (radioactive) fluoride ion is described. This transition‐metal‐free approach is high yielding, compatible with a variety of functional groups, and operated under mild reaction conditions. The conceptual advantage of this exogenous‐fluoride‐mediated transformation enables unprecedented syntheses of [¹⁸F]CF₃S‐labeled molecules from most commonly used [¹⁸F]fluoride ions. The rapid radiochemical reaction time (≤1 min) and high functional‐group tolerance allow access to a variety of aliphatic [¹⁸F]CF₃S compounds in high yields.