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

Abstract

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 article provides an overview of commonly-used labeling chemistry in the examples of clinically relevant PET tracers, and highlights most recent development and breakthroughs over the past decade with focus on ¹¹C, ¹⁸F, ¹³N, and ¹⁵O.

Graphical Abstract

1. Introduction

Positron emission tomography (PET), a non-invasive molecular imaging technique, is capable of probing biological processes in vivo, monitoring the progression of disease states, and evaluating drug treatment efficacy.^[1–4] Unlike structural and anatomical imaging techniques, including X-ray and ultrasound, PET offers functional information via the interaction between a targeted molecule bearing a positron-emitting radionuclide (‘radiotracer’) and biological system. Since only trace amounts of radioactive materials (10⁻⁶−10⁻⁹ grams) are necessary to obey the ‘tracer principle’ in such diagnostic imaging studies, it is feasible to directly monitor the biological process via PET without eliciting pharmacological effects, particularly when radiotracers with high specific activity are employed. PET radiotracers possess desired binding and physiochemical properties to interact with biological targets of interest, including receptors, enzymes and ion channels.^[5–7] The growing role of PET imaging in drug discovery efforts has prompted significant investment in novel PET ligand discovery from both industry and academic communities, yielding a steady flow of novel radioligands that showed requisite specificity toward intended biological targets to enable target engagement studies. PET imaging has also been used to examine whether the desired tissue partition of therapeutic agents are achieved and can also serve as a disease-state biomarker by detecting expression level changes in biological target between healthy and disease state, modulation of which by therapeutic agents can be used to monitor treatment efficacy in longitudinal studies.

The advance of PET is often paced by the availability and facile synthesis of targeted radiotracers.^[5] To a considerable extent, the key for successful clinical translation depends not only on the biological characteristics of the PET tracer, but also the implementation of an efficient and practical radiolabeling method to enable widespread use. Such radiochemical methods are strongly influenced by the characteristics of the PET nuclides, including chemical reactivity and half-life. Numerous review articles have captured the basic principles of PET^[1–6] and overviewed radiotracer development.^{[7, 8]} Herein, we aim to emphasize the importance of commonly-used methods, and highlight recent advances and breakthroughs in the chemistry of carbon-11, fluorine-18, nitrogen-13 and oxygen-15 in the last decade (2008–2018). The proof-of-concept application and synthesis of a diverse range of representative and clinically relevant small molecule PET pharmaceuticals are discussed. We also present unsolved challenges in PET chemistry with these radionuclides and potential area for methodology development as a unified theme to stimulate discovery research in PET chemistry.

2. Labeling methods with carbon-11

Since carbon is the backbone element in the whole spectrum of pharmaceutical molecules, isotopologue labeling using carbon-11 (¹¹C, t½ = 20.4 min) presents a unique opportunity for radiochemistry and PET tracer development since no changes of structural, biological, and pharmacological properties are anticipated after the radiolabel is implemented. The short half-life of ¹¹C requires highly-efficient transformation which usually occurs on the ultimate or penultimate step to maximize the use of rapidly-decaying radioactivity. Complementary to previous ¹¹C reviews,^[5, ^9–14] we highlight some recent developments and breakthroughs in ¹¹C chemistry with an emphasis on commonly used synthons and novel building blocks (Scheme 1). The nuclear reactions and production of the respective synthons have been reviewed elsewhere.^{[5, 12]}

Scheme 1.

Overview of ¹¹C chemistry

2.1. [¹¹C]CH₃X (X = I or OTf) chemistry

[¹¹C]CH₃I is by far the most frequently used ¹¹C-labeling agent. Nucleophilic substitution of [¹¹C]CH₃X (X = I or OTf) can generate ¹¹C-methyl heteroatomic (N, O, or S) compounds or activated carbonic ¹¹C-methylated compounds under neutral or basic conditions. This simple and direct ¹¹C-methylating method has been well applied in the synthesis of many ¹¹C-labeled tracers, including [¹¹C]PIB, [¹¹C]DASB, [¹¹C]flumazenil, [¹¹C]DTBZ, [¹¹C]MET and [¹¹C]fenoprofen (Scheme 2, A). While [¹¹C]CH₃I is satisfactory for most ¹¹C-labeling reactions, the more reactive [¹¹C]CH₃OTf (produced from [¹¹C]CH₃I with silver triflate at 200 °C) may offer an alternative solution for improved radiochemical yield (RCY) and chemoselectivity, shorter reaction time, lower reaction temperature and less precursor loading. For example, ¹¹C-N-methylation could be selectively achieved with [¹¹C]CH₃OTf under neutral conditions in the synthesis of [¹¹C]PIB without the protection of hydroxyl group.^[15] Pd-Mediated cross coupling reactions, particularly Stille and Suzuki-type, are often used to synthesize ¹¹C-labeled aryl or alkenyl tracers. Representative examples in each category include (15R)-[¹¹C]TIC, [¹¹C]MNQP and a ¹¹C-labeled mGlu1 ligand from tributylstannes,^[16] [¹¹C]celecoxib, [¹¹C]cibbi-772, and [¹¹C]UCB-J from organoborates, respectively (Scheme 2, B1). Complementary to these major approaches, proof-of-concept ¹¹C-labeling methodology studies involving Negishi^[17] / Sonogashira-type^[18] reactions, and Schwartz’s reagent,^[19] were also reported. Recently, a novel ¹¹C-acetylation method was developed using transition metal-mediated cross coupling reactions via [¹¹C]CH₃I and a CO source (Scheme 2, B2–3).^{[20, 21]}

Scheme 2.

[¹¹C]CH₃X (X=I or OTf) chemistry

2.2. [¹¹C]CO₂ chemistry

2.2.1. Formation of ¹¹C-carbonyl labeled carboxylic acids and derivatives via [¹¹C]CO₂

[¹¹C]CO₂ is the feedstock virtually for all ¹¹C chemistry and can be readily converted to other synthons in high RCYs and high specific activity.^[9, ^12] Trapping [¹¹C]CO₂ with strongly basic organometallic reagents, such as Grignard and organolithium reagents, represents an early and conventional approach to generate ¹¹C-labeled carboxylic acids (Scheme 3, A1). ¹¹C-Labeled fatty acids, such as acetic, propionic, butyric and palmitic acids, have been prepared by this method.^[12] The addition of [¹¹C]CO₂ to the lithium aldimine intermediate yielded ¹¹C-labeled α-keto acids, such as pyruvic acid.^[22] A recent example entailed [¹¹C]CO₂ insertion into organolithium (from organostannane precursor), leading to an ¹¹C-labeled of RXR- partial agonist (Scheme 3, A1).^[23]

Scheme 3.

Synthesis of ¹¹C-labeled carboxylic acids and derivatives via [¹¹C]CO₂

[¹¹C]Carboxylic derivatives including ¹¹C-labeled esters and amides, as well as ¹¹C-labeled amines could also be produced from [¹¹C]carboxymagnesium halides depending on the nature of nucleophiles and proper reducing agents if necessary (Scheme 3, A2).^{[9, 12, 24]} Representative examples include the preparation of [¹¹C]melatonin, and radiopharmaceuticals routinely used in clinical research including (+)-[¹¹C]PHNO and [¹¹C]WAY100635.

In addition, ¹¹C-labeled alkyl halides, for example, [¹¹C]benzyl iodide, can also be prepared by Grignard reaction, followed by reduction and halogenation.^[25]

Grignard and organolithium reagents are reactive species which are unstable towards air and moisture, and technical challenges of such radiosyntheses have restricted their widespread use. In 2012, Riss and Pike et al. developed a novel strategy to synthesize ¹¹C-labeled carboxylic acids and derivatives from boronic esters in the presence of a copper catalyst in high RCYs and high specific activity (Scheme 3B).^[26] The conversion was tolerant with diverse functional groups, such as halides, nitro and carbonyl groups, demonstrating a significantly broader substrate scope than that of organometallic reagents. In 2014, Vasdev and Liang et al. adopted this method to prepare [¹¹C]bexarotene under modified conditions and translated this ligand for PET-MR imaging studies in nonhuman primates.^[27] Recently, Gee and Bongarzone et al. developed a method for synthesizing ¹¹C-labeled amides from primary amines using Grignard reagents (Scheme 3C). This work utilized DBU to trap [¹¹C]CO₂, followed by the formation of ¹¹C-oxyphosphonium or [¹¹C]isocyanate intermediates, to afford ¹¹C-labeled amides upon Grignard addition.^[28]

2.2.2. Formation of ¹¹C-carbonyl labeled ureas and carbamates using [¹¹C]CO₂

The first attempt to prepare ¹¹C-labeled urea from [¹¹C]CO₂ was carried out via ¹¹C-carbonylation reaction with amines in the presence of diphenylphosphite and pyridine albeit in low RCYs. Other methods^{[9, 12]} including the use of lithium hexamethyldisilazide (LHMDS), and the formation of reactive intermediate [¹¹C]cyanamides or [¹¹C]isocyanates, offered diverse approaches to synthesize symmetrical ¹¹C-labeled ureas from [¹¹C]CO₂.

In 2006, a practical protocol to prepare unsymmetrical ¹¹C-ureas from amines and phosphinimines was reported (Scheme 4A).^[29] Phosphinimines derived from azides or primary amines generated ¹¹C-isocyanate intermediate, followed by second amine addition, to provide unsymmetrical ¹¹C-ureas in 8–49% RCYs. In 2009, Hooker and Fowler et al. reported a novel method using DBU as [¹¹C]CO₂ trapping base and carried out the synthesis of ¹¹C-labeled carbamate from amines and alkyl halides (Scheme 4B).^[30] Several radioligands based on drug scaffolds including [¹¹C]metergoline and [¹¹C]MS-275,^[31] were labeled in 25–40% RCYs. In 2011, Wilson and Vasdev et al. discovered a unified method using a phosphazene base, BEMP (as [¹¹C]CO₂ trapping base) and POCl3 (as dehydrating or chlorinating reagent) to achieve the formation of unsymmetrical ¹¹C-labeled ureas and carbamates (Scheme 4, C1).^[32] This protocol was applied in the synthesis of a broad scope of bioactive molecules,^{[9, 12]} including [¹¹C]CURB, [¹¹C]PF-04457845 and [¹¹C]SL25.1188. Recently, this process was automated by using an ‘in-loop’ synthesis module, and produced [¹¹C]SL25.1188 and [¹¹C]JNJ1661010 by flow chemistry.^[33, ^34] Another method to obtain unsymmetrical ¹¹C- labeled ureas was developed by Gee et al. in 2013 using Mitsunobu conditions (Scheme 4, C2).^[35] Both aliphatic and less reactive aromatic amines proceeded well to offer unsymmetrical ¹¹C-labeled ureas in high RCYs of 69–94%. Most noteworthy is that these [¹¹C]CO₂ fixation reactions are simple, one-pot, generally require no heating or cooling, and are easily automated. Consequently, [¹¹C]CURB and [¹¹C]SL2511.88 have been translated for human use, thereby paving the way to numerous PET radiopharmaceuticals synthesized directly from [¹¹C]CO₂.^{[9, 12]}

Scheme 4.

Synthesis of ¹¹C-labeled carbamates and ureas via [¹¹C]CO₂

Different with ¹¹C-carbonylation, Billard et al. developed a simple method to achieve ¹¹C-methylation for amines from [¹¹C]CO₂ under reducing conditions.^[36] This direct ¹¹C-labeling strategy was applied to the synthesis of [¹¹C]PIB in 45% RCY and 50 GBq/μmol molar activity.

2.3. [¹¹C]CO chemistry

2.3.1. Aromatic and activated alkyl ¹¹C-carbonylation via [¹¹C]CO

[¹¹C]CO is an established building block for the synthesis of ¹¹C-carbonyl labeled carboxylic acids, esters, amides, ketones and aldehydes via transition-metal mediated carbonylation reactions^[10–14] Pd-mediated cross coupling reaction between aryl/benzylic/methyl halides and [¹¹C]CO can provide ¹¹C-labeled carboxylic acids or esters in the presence of hydroxides or alcohols, respectively (Scheme 5, A1).^{[12, 37–39]} For example, [¹¹C]eprosartan was synthesized in 54% RCY by using the corresponding aryl iodide and [¹¹C]CO in the presence of Pd(PPh₃)₄ and Bu₄NOH.^[40] Similarly, aryl(mesityl)iodonium saltscould replace aryl halides to react with [¹¹C]CO and generate¹¹C-labeled carboxylic acids.^[41] Aryl halides could also be converted into ¹¹C-labeled aryl formyl chlorides in situ in the presence of Bu4NCl, then transformed into ¹¹C-labeled amides, esters, acids, aldehydes, alcohols and ketones.^{[42, 43]} In addition, boronate precursors via Pd-mediated transmetalation could proceed ¹¹C-carbonylation with [¹¹C]CO (Scheme 5, A2). Representative examples include a retinoid compound [¹¹C]Am80^[44] and [¹¹C]aspirin^[45] obtained from the corresponding boronates.

Scheme 5.

Pd-mediated formation of ¹¹C-labeled carboxylic acid and its derivatives via [¹¹C]CO

¹¹C-Labeled amides could also be obtained from appropriate primary or secondary amines in Pd-mediated cross coupling reactions between aryl halides and [¹¹C]CO.^[10–14] Several representative radiotracers are shown in Scheme 5, B1. This is one of three primary methods to access ¹¹C-labeled amides, in addition to [¹¹C]CO₂ (via acylation and aminolysis) and [¹¹C]CN (via controlled hydrolysis) methods. Since [¹¹C]CO has limited solubility in organic solvents, efficient radioactive gas trapping in the reaction system is challenging. Several novel strategies were developed to address this problem,^{[11, 14]} including use of a high-pressure reactor, continuous flow microreactor, gas-liquid segmented microfluidics, use of palladium dimer catalyst or NHC ligand, trapping [¹¹C]CO by Pd catalyst, NHC ligand, borane, and copper(I) complex, xenon gas carrier, and improved methods to produce [¹¹C]CO.^[46–48] Among these methods, a recent example by Skrydstrup and Antoni et al. highlighted the use of [¹¹C]CO in a simple low-pressure vessel with pre-activated aryl-Pd species as stoichiometric reagents and produce well-functionalized radioligands in high RCYs (Scheme 5, B2).^[49] The same authors also applied this strategy in the N-¹¹C-acetylation of peptides with [¹¹C]CO and bisphosphine-ligated Pd complexes (Scheme 5, B3).^[50] Several representative N-¹¹C-acetylated bioactive peptides, such as [¹¹C]lacosamide, [¹¹C]acetyl LULUPhol and [¹¹C]acetyl cRGDfK were obtained in high RCYs of 33–46% and high molar activity of 281–404 GBq/μmol.^[50]

The synthesis of ¹¹C-carbonyl labeled ketones can be accomplished by [¹¹C]CO-involved three-component Stille-type cross coupling reactions (Scheme 6A).^{[10–14, 51,52]} For example, a potential PET radioligand for histamine subtype 3 receptors, was ¹¹C-labeled by this method using the corresponding arylstannane, aryl iodide and [¹¹C]CO.^[52] [¹¹C]Benzaldehyde could be obtained when Et₃SiH was employed instead of an organotin reagent.^[51] Furthermore, Suzuki-type reactions were also capable of providing ¹¹C-carbonyl labeled ketones (Scheme 6B).^[53] The products were obtained in the range of 10–70% RCYs and high molar activity (>150 GBq/μmol).

Scheme 6.

Pd-mediated formation of ¹¹C-ketones and aldehydes via [¹¹C]CO

2.3.2. ¹¹C-Carbonylation of nonactivated aliphatic substrates via [¹¹C]CO

Despite the exciting advances in the Pd-mediated ¹¹C- carbonylation reactions with [¹¹C]CO, the scope is commonly limited to aryl, alkenyl, methyl and benzyl substrates without liability of inclined β-H elimination from ensuing oxidative Pd(II) complex. To expand substrate chemotype, other transition metals or radical-mediated methods were used to activate alkyl halides containing β-hydrogen atoms. In 2016, Rahman et al. developed a Ni-mediated method for the synthesis of ¹¹C-carbonyl labeled alkyl amides starting from non-activated alkyl iodides (Scheme 7A).^[54] Cyclic or acyclic alkyl iodides were converted to ¹¹C- carbonyl labeled amides in 33–90% RCYs. Alkyl iodides could also be utilized in free radical-mediated reactions with [¹¹C]CO, to generate ¹¹C-carbonyl labeled carboxylic acids, esters and amides in good RCYs (44–76%) with high molar activity (Scheme 7B).^[55–57]

Scheme 7.

¹¹C-Carbonylation of nonactivated aliphatic substrates via [¹¹C]CO

2.3.3. Synthesis of ¹¹C-carbonyl labeled urea and carbamate via [¹¹C]CO

Complementary to [¹¹C]CO₂ and [¹¹C]COCl₂ chemistry, Rh-mediated ¹¹C-carbonylation reactions convert aryl azides and [¹¹C]CO into the corresponding Rh-coordinated ¹¹C-isocyanates, which subsequently form ¹¹C-carbonyl labeled ureas and carbamates, respectively (Scheme 8).^[58] This method was applied in the preparation of a wide range of ¹¹C-compounds, including ¹¹C-labeled VEGFR-2/PDGFR-β dual inhibitors,^[59]

Scheme 8.

Formation of ¹¹C-carbonyl labeled ureas and carbamates via [¹¹C]CO

[¹¹C]phenytoin,^{[60] 11}C-labeled sulfonyl ureas and carbamates,^[61, ^62] and ¹¹C-labeled hydroxyurea derivatives.^[63] in addition, Se-mediated ¹¹C-carbonylation of amines and alcohols with [¹¹C]CO offered an alternative method for the preparation of ¹¹C-carbonyl labeled carbamoyl compounds.^[64]

2.4. [¹¹C]CN chemistry

2.4.1. Synthesis of ¹¹C-labeled aliphatic nitriles and derivatives

While aromatic nitriles are often found as key scaffolds and pharmacophores in drug molecules, aliphatic nitriles typically exist as intermediates for the preparation of carboxylic acids, amides, amines, and related derivatives. This principle is also applicable for chemistry with [¹¹C]CN. ¹¹C-Labeled alkyl nitriles are commonly prepared by nucleophilic substitution or addition reactions with H[¹¹C]CN as the reagent. The most frequent derivatization is to generate ¹¹C-carboxylic acids or derivatives (Scheme 9A). For example, [¹¹C]lactic acid was produced by [¹¹C]CN addition to acetaldehyde or substitution of aldehyde- bisulfite adduct, followed by hydrolysis. The same protocol could be also applied in the synthesis of [¹¹C]valine (via hydrolysis), [¹¹C]glutamine (via aminolysis) and [¹¹C]dopamine (via reduction). Another method to obtain ¹¹C-labeled amino acids involved the formation of [¹¹C]hydantoin, which was produced via the Bücherer-Bergs reaction from ketones or aldehydes (Scheme 9B). Then [¹¹C]hydantoin was converted to the corresponding ¹¹C- labeled amino acids via hydrolysis in basic conditions. Furthermore, ring-opening of aziridine with [¹¹C]CN also led to alkyl-¹¹CN compounds, which could be converted to ¹¹C-labeled carboxylic acids in 30–40% RCYs (Scheme 9C).^[65]

Scheme 9.

Formation of alkyl-¹¹CN and its derivatives

2.4.2. Formation of ¹¹C-labeled aromatic nitriles and derivatives

Pioneered with the nucleophilic substitution of Cr(CO)3 complexes with [¹¹C]CN, aryl-¹¹CN formation was gradually replaced by Pd- or Cu-mediated cross coupling reactions attributed to more extensive substrate scope and higher reaction efficiency (Scheme 10, A1).^[12] Representative examples of Pd- mediated reactions include [¹¹C]AZD9272, and compounds derived from aryl-¹¹CN, like [¹¹C]NAD-299. The recent discovery of biaryl phosphine ligands for Pd catalysts, such as t-BuXPhos, further advanced new aromatic ¹¹CN chemistry. In 2015, Hooker and Buchwald et al. developed a Pd-mediated ¹¹C-cyanation of aryl halides/triflates at ambient temperature with rapid reaction rate (<1 min; Scheme 10, A2).^[66] These biaryl phosphine ligands, e.g., t-BuXPhos or BrettPhos, were the key to stabilize Pd-aryl complex and accelerate transmetalation and reductive elimination under mild reaction conditions. These authors further extended this concept to the labeling of cysteine-containing peptides via a sequential Pd-mediated C-S and C-¹¹CN bonding formation in one-pot.^[67] The formal ‘nucleophile-nucleophile coupling’ provided ¹¹C-labeled peptides in high RCYs (10–50%). Arylboron

Scheme 10.

Formation of aromatic ¹¹CN and its derivatives

Alternative to Pd-mediated ¹¹C-cyanation, Ponchant et al. found that [¹¹C]CN could be trapped by copper to produce Cu[¹¹C]CN in situ, which was then reacted with aryl halides to synthesize ¹¹C-labeled aryl nitriles under high temperature (150250 °C).^[68] compounds and arylstannanes can also be used as precursors in the Cu-mediated cyanation. In 2017, Liang and Vasdev et al. developed a ¹¹C-cyanation methodology that takes advantage of aryl boronic acids. This strategy could be realized in aqueous solutions and was compatible with a wide range of aryl boronic precursors, resulting in diverse radiolabeled compounds in 9–70% RCYs (Scheme 10, B2).^[69] In 2018, Scott and Sanford et al. further extended labeling precursors to other arylboron compounds and arylstannanes using Cu(II)(OTf)₂. This method was compatible with a broad range of substrates. For example, [¹¹C]perampanel was prepared in 10% RCY and 70 GBq/μmol molar activity using an automated radiosynthesis module (Scheme 10, B2).^[70]

2.5. Miscellaneous ¹¹C synthons and reagents

Some commonly used / recent developed ¹¹C synthons and reagents prepared by 1–4 step reactions from [¹¹C]CO₂ are highlighted in Scheme 11 to demonstrate the diversity and creativity of ¹¹C chemistry.

Scheme 11.

Selected ¹¹C Synthons prepared by 1–4 step reactions

Selected examples of recent ¹¹C-labeled building blocks are described below. [¹¹C]HCHO, produced from [¹¹C]CH₃OH oxidation, has been applied in reductive methylations, ringclosure reactions, electrophilic aromatic substitutions and others.^{[12, 13]} In 2008, Hooker et al. developed a new method to synthesize [¹¹C]HCHO from [¹¹C]CH₃I with trimethylamine N- oxide (Scheme 12A).^[71] Several ¹¹C-labeled tracers including [¹¹C]vabicaserin and [¹¹C]WAY-163909, were efficiently synthesized via the Pictet-Spengler reaction using [¹¹C]HCHO.^[72] [¹¹C]CS₂ was first prepared from [¹¹C]CO₂ and H₂S in low RCYs.^[73] In 2012, Miller et al. developed a novel method to produce [¹¹C]CS₂ by gas phase reaction between [¹¹C]CH₃I and a thionating agent P₂S₅.^[74] Then they improved the method by switching the thionating reagent from P₂O₅ to elemental sulfur (Scheme 12B).^[75] [¹¹C]CS2 was found to rapidly react with a broad spectrum of primary amines to give ¹¹C-labeled thiocarbonyl thioureas, including [¹¹C]tanaproget, in high RCYs and high molar activity. In 2017, Pike et al. described a new type ¹¹C-labeled agent [¹¹C]CF₃H, based on the fluorination of [¹¹C]CH₄ with CoF₃ (Scheme 12C).^[76] This ¹¹C-labeled reagent was applied to demonstrate a wide range of trifluoromethylations, including nucleophilic additions with ketones, cross-coupling reactions with aryl boronic acids, aryl iodides and aryl diazonium salts via Cu[¹¹C]CF₃ generated in situ. ¹¹C-Labeled trifluoromethyl arenes, including [¹¹C]flutamide and [¹¹C]lefunomide, exhibited high RCYs and high molar activity (>200 GBq/μmol). In particular, the molar activity of ¹¹C-labeled trifluoromethyl arenes far exceeded its ¹⁸F- counterpart (aryl [¹⁸F]CF₃), providing a viable access to radiolabel mutlifluoromethylated compounds in high molar activity. Diverse methods to prepare [¹¹C]COCl₂ from [¹¹C]CO₂ or [¹¹C]CH₄ have been developed since the 1970s. Among these methods, an efficient automated [¹¹C]COCl₂ synthesis with high RCYs (>80%) was reported in 2010.^[77] [¹¹C]COCl₂ is an effective reagent to synthesize ¹¹C-labeled ureas and carbamates via [¹¹C]isocyanate or [¹¹C]carbamoyl chloride intermediates. A diverse range of ureas and carbamates, including ¹¹C-labeled 18-β-glycyrrhetinic acid derivative,^[78] [¹¹C]MFTC,^[79] [¹¹C]SAR127303^[80] and [¹¹C]MAGL-0519,^[81] were efficiently obtained via [¹¹C]COCl₂.

Scheme 12.

Miscellaneous ¹¹C-synthons and reagents

3. Labeling methods with fluorine-18

Fluorine-18 (¹⁸F) is the most widely used PET nuclide attributed to the extensive clinical use of 2-deoxy-2-[¹⁸F]fluoro-D- glucose ([¹⁸F]FDG) in the diagnosis of cancers, cardiovascular and neurological diseases. Fluorine-18 (as [¹⁸F]fluoride) is most commonly produced via the ¹⁸O(p,n)¹⁸F nuclear reaction in high radioquantity and high specific activity, and has a relatively long half-life (109.8 min) compared to ¹¹C, which allows for multi-step synthesis, extended imaging protocols, and off-site use in satellite PET facilities without a cyclotron. These favorable characteristics provide a strong stimulus to develop novel ¹⁸F-labeled compounds, and efficient and translational radiofluorination methods. Complementary to previous fluorine-18 reviews,^{[16, 82–88]} we focus on the recent development and breakthroughs in the nucleophilic and electrophilic reactions with ¹⁸F (Scheme 13). Indirect ¹⁸F-labeling methods, i.e., reactions involved with ¹⁸F- building blocks, are discussed elsewhere.^{[88, 89]}

Scheme 13.

Overview of ¹⁸F chemistry.

3.1. Aliphatic ¹⁸F-fluorination with nucleophilic [¹⁸F]fluoride

3.1.1. Aliphatic nucleophilic substitution

Aliphatic nucleophilic substitution with [¹⁸F]fluoride is a reliable method that has been commonly used to generate Csp3- ¹⁸F bonds in high RCYs and high specific activity. The most common reaction of this type involves the substitution of an adequate leaving group that is susceptible to displacement by [¹⁸F]fluoride (Scheme 14A). These leaving groups include -triflate (-OTf), -tosylate (−OTs), -mesylate (−OMs) and halides, with a decreasing order of leaving ability (−OTf > −OTs ~ −OMs > −I > −Br > −Cl). Another type of aliphatic nucleophilic ¹⁸F-fluorination entails the addition of [¹⁸F]fluoride into strained cyclic substrates, for example, ring opening reactions of epoxides and aziridines (Scheme 14B). The potential regio- and stereo-genicity makes this method attractive for the radiosynthesis of PET tracers, including clinically-relevant [¹⁸F]FES and [¹⁸F]FLT. Complementary to one-step nucleophilic [¹⁸F]fluoride displacement approaches, indirect methods are also widely used,^[89–91] which typically involve the utilization of [¹⁸F]fluoroalkyl prosthetic groups to conjugate with O, N, or S-nucleophiles, especially when the corresponding precursors are labile during ¹⁸F-fluorination (Scheme 14C).

Scheme 14.

Common strategies for synthesis of ¹⁸F-alkyl groups

A large number of ¹⁸F-labeled PET tracers are prepared through aliphatic nucleophilic ¹⁸F-fluorination and can be categorized into four major chemotypes, including unbranched and branched acyclic alkyl-¹⁸F, cyclic alkyl-¹⁸F, and alkyl-¹⁸F with [¹⁸F]fluorine atom at activated positions (Scheme 15). The first common form is the unbranched acyclic alkyl-¹⁸F. Representative examples include [¹⁸F]FMeNER-D2, [¹⁸F]FMISO, [¹⁸F]FET, [¹⁸F]fallypride and [¹⁸F]florbetapir (Scheme 15A). The two deuterium (D) atoms in [¹⁸F]FMeNER-D2 are introduced to improve metabolic stability and reduce the rate of in vivo defluorination during PET studies.^[92] An rigorous overview of ¹⁸F- tracer metabolism can be found elsewhere.^[93] The second chemotype entails branched acyclic alkyl-¹⁸F (Scheme 15B), which includes but is not limited to [¹⁸F]iNOS-9, [¹⁸F]FTHA, and [¹⁸F]FDS. Cyclic alkyl-¹⁸F is another common chemotype (Scheme 15C), including the most widely used PET radiopharmaceutical [¹⁸F]FDG, and other tracers, like [¹⁸F]FES, [¹⁸F]FLT, [¹⁸F]FACBC, and [¹⁸F]FP. In the last category, ¹⁸F- fluorination takes advantage of activated positions on the molecule, including the benzylic, allylic or α-position of the carbonyl group, to facilitate ¹⁸F-incorporation (Scheme 15D). A few representative examples include [¹⁸F]SP203, [¹⁸F]AB5186, ¹⁸F-labeled allyl, propargyl, and α-carbonyl compounds, such as 4-[¹⁸F]fluoroglutamine and [¹⁸F]PBR06.

Scheme 15.

Representative chemotypes of aliphatic [¹⁸F]fluorides

Compared with nucleophilic ¹⁸F-fluorination reactions which are often conducted in polar aprotic solvents, Chi and co-workers used ionic liquids^[94] and unusual protic solvents^[95] to improve ¹⁸F- labeling efficiency (Scheme 16, A1). These conditions could not only dramatically increase ¹⁸F reactivity and reaction rate, but also decrease the formation of undesired products, such as alkenes, alcohols or ethers. For instance, [¹⁸F]FP-CIT was synthesized in 36% RCY under new conditions containing tBuOH, in contrast to only 3% RCY using CH₃CN as a solvent (Scheme 16, A2).^[96] These new labeling conditions were also applied in the synthesis of several radioligands, including [¹⁸F]FP-CIT, [¹⁸F]FLT and [¹⁸F]PF05270430 (Scheme 16, A3).^[97] The conversion of alcohols to alkyl-¹⁸F typically involve a two-step sequence, namely, the formation of alcohol-derived leaving groups, such as -OTs or - OMs, and the subsequent aliphatic ¹⁸F-fluorination. In 2015, Doyle et al. reported a ‘one-pot’ direct synthesis of alkyl fluorides from the corresponding alcohols with 2-pyridinesulfonyl fluoride (PyFluor), a new deoxyfluorination reagent (Scheme 16B).^[98] As proof of concept, [¹⁸F]FDG was achieved by ¹⁸F-deoxyfluorination of O-protected carbohydrate in 15% radiochemical conversion (RCC).

Scheme 16.

Unconventional aliphatic ¹⁸F-fluorination reactions

An azeotropic [¹⁸F]fluoride drying is nearly always employed to ensure high reactivity of ¹⁸F under anhydrous conditions. However, this process may lead to decreased RCY/molar activity attributed to prolonged reaction and/or surface adsorption. In 2015, van Dam and Sergeev et al. developed TiO₂-catalyzed ¹⁸F- fluorination of tosylated precursors in highly aqueous medium without the need of [¹⁸F]fluoride drying (Scheme 16C).^[99] TiO₂ was the key in the ¹⁸F-fluorination. First, solvated [¹⁸F]fluoride in water was adsorbed at the active surface of TiO₂, thus enhancing fluorine-18 reactivity. Synergistically, TiO₂ also activated the tosylate precursor via Ti-O coordination with two oxygen atoms of the sulfonyl group.

¹⁸F-Fluorination was not merely limited to organic reactions. O’Hagan et al. developed a novel ¹⁸F-labeling protocol using enzymatic biosynthesis (Scheme 16D). ¹⁸F-Fluorination of (S)- adenosyl-L-methionine (SAM) to 5’-[¹⁸F]fluoro-5’-deoxyadenosine (5’-[¹⁸F]FDA) was carried out smoothly by fluorinase with up to 95% RCY.^[100] Recently, they further extended this enzymatic ¹⁸F- fluorination to obtain 5’-[¹⁸F]fluorodeoxy-2-ethynyladenosine labeled RGD peptides in 12% RCY and no radiodefluorination was observed in PET imaging studies.^[101]

3.1.2. Transition metal-mediated aliphatic ¹⁸F-fluorination

Aliphatic nucleophilic ¹⁸F-fluorination is usually performed in basic conditions at high temperature; however, these conditions may not be compatible with well-functionalized molecules, resulting in the formation of undesired side products. Transition metal-mediated aliphatic ¹⁸F-fluorination may thus provide an alternative to generate alkyl-¹⁸F bonds under mild conditions. In 2011, Gouverneur and Brown et al. reported Pd-catalyzed fluorination of highly active allyl p-nitrobenzoates with TBAF at room temperature.^[102] Allylic ¹⁸F-fluorination was also achieved using [¹⁸F]TBAF (Scheme 17, A1). In the same year, Nguyen et al. developed Ir-catalyzed allylic fluorination of trichloroacetimidates.^[103] The ¹⁸F-labeling reaction was conducted with K[¹⁸F]F/K₂₂₂, and the ensuing allyl [¹⁸F]fluoride was achieved in 38% RCY (Scheme 17, A2). In 2013, Gouverneur and Brown et al. reported another Ir-catalyzed fluorination of allyl carbonates,^[104] in which a wide range of branched, linear (E)- and (Z)- allyl substrates were labeled with [¹⁸F]Et4NF in 8–76% RCYs (Scheme 17, A3).

Scheme 17.

Transition metal-mediated aliphatic ¹⁸F-fluorination

Ring-opening of epoxides with [¹⁸F]fluoride is a stereogenic method to prepare ¹⁸F-tracers. In 2014, Doyle et al. developed an enantioselective ¹⁸F-fluorination of epoxides with chiral [¹⁸F](salen)CoF (Scheme 17B).^[105] The group also developed a dimeric chiral cobalt catalyst to overcome the challenges associated with epoxide substrates bearing Lewis basic nitrogen or α-branching substituents. Several PET tracers were synthesized by this method, including [¹⁸F]THK-5105 (85% ee) and [¹⁸F]FMISO (90% ee).

Groves and Hooker et al. developed a novel Mn-catalyzed benzylic C-H ¹⁸F-fluorination method (Scheme 17C).^[106] Several fluorinated drug moieties, including a [¹⁸F]celecoxib analog and a ¹⁸F-labeled fingolimod, were efficiently labeled. The authors also extended this method to non-activated aliphatic substrates.^[107] The use of a more reactive Mn-porphyrin complex Mn(TPFPP)OTs was essential to enable efficient transformation. A diverse range of bioactive molecules was efficiently labeled, including [¹⁸F]ACPC (48% RCC) and a [¹⁸F]flutamide analog.

Lu and Li et al. recently reported Ag-promoted intramolecular cyclization of unsaturated carbamates using [¹⁸F]fluorobenziodoxole.^[108] A range of ¹⁸F-labeled heterocycles were achieved by using this method but the efficiency of ¹⁸F-labeling needs to be further improved (RCYs < 10%). Szabó et al. also reported a metal-free intramolecular cyclization of unsaturated amides with isolated [¹⁸F]fluorobenziodoxole.^{[109] 18}F-Fluorocyclization of a wide range of o-styrilamides were performed with high RCCs (54–90%).

3.2. Aromatic ¹⁸F-fluorination with nucleophilic [¹⁸F]fluoride

3.2.1. Aromatic nucleophilic substitution

Aromatic nucleophilic substitution (S_NAr) with [¹⁸F]fluoride represents a direct and commonly used method to form C_Sp2-¹⁸F bonds (Scheme 18A). An optimal precursor will generally bear both a leaving group and an activating group (usually electron- withdrawing) in the ortho or para position to facilitate the S_NAr reaction by stabilizing the Meisenheimer complex. Representative PET tracers are shown in Scheme 18B. Alternatively, molecules with non-activating substituents could also be synthesized through S_NAr conversion of arenes with electron-withdrawing groups, followed by post-S_NAr functional group manipulations.^{[110, 111]} Nitrogenous heteroarene, such as pyridine, is electron-deficient than its homoarenes counterpart, which provides a unique opportunity for ¹⁸F-labeling via S_NAr without the need of activating groups. A wide range of ¹⁸F-heteroarenes (particularly 2- [¹⁸F]fluoropyridine), were synthesized by this approach (Scheme 18C).

Scheme 18.

Aromatic nucleophilic substitution (S_NAr) with [¹⁸F]fluoride ion

Efficient ¹⁸F-labeling via S_NAr requires the presence of an activating group and a leaving group on the arene, which significantly limits the substrate scope. To overcome this challenge, the search for novel precursors carrying new activating and/or leaving groups continues. Recently, research efforts have been made in the development of novel sulfur-based precursors. The first example was demonstrated by Maeda et al. using aryldimethylsulfonium salts in 1987.^[112] However, the formation of undesired methyl [¹⁸F]fluoride made this method unfavorable for labeling arenes. In 2012, Ametamey et al. developed triarylsulfonium salts as a new class of precursors for ¹⁸F-labeling arenes (Scheme 19, A1).^{[113] 18}F-fluorination preferred to occur on the relatively electron-deficient aryl group and the remaining diarylsulfonium group served as the leaving group. In 2015, Arstad et al. extended the substrate scope to electron-rich arenes by using diarylsulfonium bearing para-methoxyphenyl groups as the leaving group (Scheme 19, A2).^[114] Besides triarylsulfonium salts, diaryl sulfoxides were also potential precursors for ¹⁸F- labeling reactions discovered by Pike et al. in 2016.^[115] A higher reaction temperature (150–200 °C) was required probably attributed to low reactivity of diaryl sulfoxides. Electron-deficient diaryl sulfoxides offered products in high RCCs, such as 1-[¹⁸F]fluoro-4-nitrobenzene (78%), whereas the labeling of electron-rich diaryl sulfoxides remained a challenge.

Scheme 19.

Unconventional aromatic nucleophilic substitution (S_NAr) with [¹⁸F]fluoride

Murphy et al. developed N-arylsydnones as novel precursors for ¹⁸F-labeling of arenes bearing electron-deficient substituents (Scheme 19B).^[116] It was found that the sydnone was not only inductively more electron-withdrawing than the nitro group, but also positioned away from the aryl plane and limited full resonance with the arene. This makes the sydnone a weak anion stabilizer as an excellent activating group for ¹⁸F-incorporation.

Phenols are common building blocks in organic synthesis, which makes ¹⁸F-deoxyfluorination an attractive strategy to achieve ¹⁸F-labeled arenes. Ritter and Hooker et al. developed a novel ¹⁸F-fluorination method of phenols based on a concerted nucleophilic aromatic substitution (CS_NAr) mechanism (Scheme 20A).^[117] This reaction involved the formation of a uronium intermediate, which was distinct from the Meisenheimer complex in the conventional S_NAr. Electron-deficient phenols were efficiently converted to aryl-¹⁸F in high RCCs (>80%). Recently, Ritter and Hooker et al. further utilized a ruthenium catalyst via η⁶ π-complex for ¹⁸F-deoxyfluorination of electron-rich phenols (Scheme 20B).^[118]

Scheme 20.

¹⁸F-Deoxyfluorination of phenols via concerted S_NAr

Different with ¹⁸F-deoxyfluorination, Gouverneur et al. reported a novel method for ipso ¹⁸F-substitution of t-butyl group at the para position of phenols.^[119] As an alternative S_NAr-type pathway, this reaction involved two steps, i.e., de- aromatization/fluorination under oxidative conditions, and re- aromatization under acidic conditions. A series of 4-tert- butylphenols were converted to 4-[¹⁸F]fluorophenols using PhI(OAc)₂ as the oxidant with 7–20% RCYs.

3.2.2. ¹⁸F-Fluorination of hypervalent iodine(III) compounds

Despite significant advances in the ¹⁸F-labeling of arenes via the S_NAr method, there is an unmet need for efficient ¹⁸F- fluorination methods of non-activated arenes. The low efficiency of using Balz-Schiemann and Wallach reactions in the ¹⁸F- labeling shifted the research focus initially towards the application of trimethylammonium triflates^[120] and more recently major advances have been made with hypervalent iodine(III) based precursors. The first example of diaryliodonium salts as precursors in the synthesis of aryl-¹⁸F was reported by Pike et al. (Scheme 21A),^[121] in which arenes with electron-deficient or -rich substituents showed high ¹⁸F-labeling efficiency. The relatively electron-deficient aryl moiety of the corresponding salt was preferrably labeled by fluorine-18. To achieve high regioselectivity of unsymmetrical diaryliodonium salts, Coenen et al. developed a novel class of aryl(2-thienyl)iodonium salts and demonstrated ¹⁸F- labeling in a highly regioselective manner (Scheme 21B).^[122] Specifically, ¹⁸F-fluorination of aryl(2-thienyl)iodonium salts preferred to occur on the counterpart. An ortho substitution on the aryl group of diaryliodonium salts has substantial effects on the regioselectivity, with the preference of radiofluorination occurs on the ortho-substituted arene (Scheme 21C).^[123] Mechanistically, a trigonal bipyramidal iodine intermediate was proposed during ¹⁸F- fluorination of diaryliodonium salts (Scheme 21D). While the two aryl groups could rapidly exchange their positions via Berry pseudorotation process, steric bulky ortho-substituted aryl group was situated in an equatorial position to minimize the steric repulsion, leading to a favored reductive elimination pathway to form an Csp²-¹⁸F bond on the equatorial arene in both monomeric and oligomeric state. ^{[123, 124]}

Scheme 21.

¹⁸F-Fluorination of diaryliodonium salts

Recent optimization of reaction conditions and involvement of transition metal catalysts have advanced diaryliodonium salts based radiofluorinations. In 2012, DiMagno and Snyder et al. reported a new method for ¹⁸F-fluorination of diaryliodonium salts in nonpolar solvents with high RCYs.^[125] In particular, diaryliodonium triflate and [¹⁸F]fluoride were first dissolved in a polar aprotic solvent (e.g., MeCN) to facilitate ion exchange between OTf and ¹⁸F. After solvent removal, a nonpolar medium (e.g., toluene) was then added for reductive radiofluorination, which was beneficial to inhibit side reactions, including internal electron transfer and disproportionation of diaryliodonium salts. The new method has been used in the synthesis of several ¹⁸F- pharmaceuticals,^[126] including [¹⁸F]FDOPA, [¹⁸F]mFBG, [¹⁸F]FDA, and [¹⁸F]flutemetamol.

In 2014, Scott and Sanford et al. reported Cu-mediated ¹⁸F- fluorination of mesityl(aryl)iodonium salts (Scheme 22A).^[127] Contrary to the “ortho effect”, ¹⁸F-Csp² reductive elimination occurred on the counterpart of steric bulky mesityl group to allow access to a variety of electron-rich, -neutral and -deficient ¹⁸F- arenes. Recently, the same authors improved their method by the formation of electron-rich mesityl(aryl)iodonium salts in situ, which offers a potential solution to synthesize electron-rich aryl-¹⁸F bonds without the need of isolation for certain unstable electron- rich diaryliodonium salts.^[128]

Scheme 22.

Recent application in the ¹⁸F-fluorination of diaryliodonium salts

The traditional method for the preparation of diaryliodonium salts was limited to oxidation of aryl iodides, followed by ligand exchange. In 2016, Liang and Liu et al. developed a new one-pot method to synthesize aryl(isoquinoline)iodonium salts via the mesoionic carbene silver complex (Scheme 22B).^[129] Radiofluorination of a board range of aryl(isoquinoline)iodonium salts were achieved with [¹⁸F]Et₄NF in 25–65% RCYs. As proof of concept, a ¹⁸F-labeled natural product, [¹⁸F]fluoroaspergillitine, was achieved in 10% RCY with molar activity of 37 GBq/μmol.

In all, attributed to its high efficiency in the ¹⁸F-labeling of arenes, particularly for the substrates without proper activating substituents, diaryliodonium salts method has been well applied in the synthesis of a wide range of clinically relevant PET tracers (Scheme 22C).^[126]

Among the methods for ¹⁸F-labeling of hypervalent iodine(III) species, little attention was paid to other type λ³-iodine compounds until radiofluorination of (diacetoxyiodo)arenes^[130] and aryliodonium ylides were developed in recent years. Notably, the latter method has shown excellent progress to achieve unprecedented radiofluorination of non-activated arenes.

In an early report by Ermert et al. in 2014, aryliodonium ylides with Meldrum acid auxiliaries were developed for ¹⁸F-labeling of arenes.^[131] In the same year, Liang and Vasdev et al. independently developed a novel class of spirocyclic iodonium ylides (SCIDY) and demonstrated regioselective radiofluorination of non-activated arenes (Scheme 23A).^[132] SCIDY with cyclopentyl auxiliary gave the highest 85% RCC in the ¹⁸F- fluorination of biphenyl iodonium ylides. Using this auxiliary, a wide range of [¹⁸F]fluoroarenes were readily achieved via SCIDY in high RCYs. Thermal stability of aryliodonium ylides highly depended on auxiliary substitution, which showed a positive correlation with ¹⁸F-incorporation efficiency. A second generation auxiliary, namely SPIAd (spiroadamantyl-1,3-dioxane-4,6-dione), developed by the same authors, outperformed all the other auxiliaries of aryliodonium ylides in stability tests and exhibited highly efficient ¹⁸F-labeling capability (Scheme 23B).^[133] In addition, Riss et al. reported an improved PPh₃-assisted ¹⁸F- fluorination of aryliodonium ylides, which showed increased fluorination yield and reaction rate.^[134]

Scheme 23.

¹⁸F-Fluorination of aryliodonium ylides

¹⁸F-Labeling of aryliodonium ylides demonstrated substantially improved regioselectivity over diaryliodonium salts method.^[133] The auxiliary group has a preference for the axial position and aryl group takes the equatorial position. The calculation results showed that undesired Csp³-F reductive elimination had ca. 25 kcal/mol higher barrier than favorable Csp²- F pathway, which explained the unique regioselectivity in the ¹⁸F- labeling of aryliodonium ylides (Scheme 23C).

As radiofluorination of aryliodonium ylides is an efficient and metal-free method for non-activated arenes, a diverse range of clinically relevant radiopharmaceuticals and ¹⁸F-labeled drug scaffolds were obtained by this route (Scheme 24).^{[81, 132, 133, 135–143]} It is noteworthy that [¹⁸F]FPEB synthesized via SCIDY technology was fully automated, resulting in a substantial improvement (3–10 fold) in RCYs and molar activity compared with the traditional S_NAr method, and has been validated for human use.^[144]

Scheme 24.

Representative examples for ¹⁸F-fluorination of aryliodonium ylides

3.2.3. Transition metal-mediated aromatic ¹⁸F-fluorination

Significant advances have been achieved in the aromatic radiofluorination using transition metals with enhanced reactivity, selectivity and tolerance towards functional groups, which may provide an alternative approach to access [¹⁸F]fluoroarenes. In 2011, Ritter and Hooker et al. developed a novel aromatic ¹⁸F- fluorination method based on Pd(IV) complex (Scheme 25A).^[145] The highly fluorophilic Pd species 1 and [¹⁸F]fluoride generated Pd-¹⁸F complex 2, which not only served as an electrophilic ¹⁸F- fluorination reagent but also oxidized aryl-Pd(II) complex 3 to aryl- Pd(IV)-¹⁸F complex, to afford [¹⁸F]fluoroarenes after reductive elimination. This method was applied in the synthesis of [¹⁸F]fluoroestrone, [¹⁸F]paroxetine and a ¹⁸F-labeled 5-HT_2C agonist (> 1% RCYs).^{[145, 146]} In 2012, Ritter et al. developed another oxidative ¹⁸F-fluorination by using aryl-Ni(II) complexes (Scheme 25B).^[147] The ¹⁸F-Ni(II) complex occurred directly with aqueous [¹⁸F]fluoride at room temperature. Both aryl and alkenyl [¹⁸F]fluoride could be obtained in high RCYs and representative examples include 3-[¹⁸F]fluorobenzamide, [¹⁸F]fluorophenylalanine, 5-[¹⁸F]fluorouracil and [¹⁸F]MDL100907, as well as several ¹⁸F-labeled aromatic amino acids, 6-[¹⁸F]FDA, 6-[¹⁸F]FDOPA, 6-[¹⁸F]FMT under an improved ‘low base’ protocol.^[148–150]

Scheme 25.

Pd- or Ni-mediated aromatic fluorination with [¹⁸F1fluoride

Copper catalysts are widely used in the aromatic fluorination reactions with aryl boronates and arylstannanes. In 2014, Gouverneur et al. developed Cu-mediated ¹⁸F-fluorination of aryl boronic esters (e.g., aryl-BPin) with [¹⁸F]fluoride (Scheme 26A). The reaction with aryl-BPin precursors was performed in the presence of Cu(OTf)2Py4 and O₂, the latter of which was necessary and beneficial for ¹⁸F-incorporation.^{[151, 152]} Besides aryl-BPin and copper triflate pyridine system, Sanford and Scott et al. independently developed Cu-mediated ¹⁸F-fluorination from aryl boronic acid precursors (Scheme 26B).^[153] The reaction was mediated by Cu(OTf)₂ in the presence of pyridine with high ¹⁸F- labeling efficiency.

Scheme 26.

Cu-mediated aromatic fluorination with [¹⁸F]fluoride

Arylstannanes are excellent arylating reagents in transmetalation processes, leading them as potential labeling precursors for Cu-based radiofluorinations. In 2016, Murphy et al. reported copper-mediated oxidative fluorination of arylstannanes with fluoride using TBAT and copper(II) triflate.^[154] In the same year, Sanford and Scott et al. independently developed Cu- mediated radiofluorination of arylstannanes (Scheme 26C).^[155] The reaction was performed with [¹⁸F]fluoride in the presence of pyridine, and compatible with electron-rich and -deficient arylstannanes, as well as vinyl substrates.

These Cu-mediated ¹⁸F-labeling methods from boron or tin precursors have been applied in the synthesis of a number of clinical relevant PET ligands under original or improved ‘low base’ conditions.^[156] Representative examples from boron esters, boronic acids and arylstannanes are shown in Scheme 27, respectively^{[151–153, 155, 157]}

Scheme 27.

Representative examples for Cu-mediated aromatic ¹⁸F- fluorination

3.3. Formation of ¹⁸F-labeled multifluoromethyl motifs from nucleophilic [¹⁸F]fluoride

3.3.1. ¹⁸F-Labeled aryl-CF₃/CF₂H/OCF₃/OCF₂H groups via halogen-¹⁸F exchange

Continuous development of CF₃/CF₂H-containing pharmaceuticals provides a strong impetus to develop novel radiochemical methods to label these groups that were previously not accessible to drug discovery and PET tracer development. Halogen exchange of CF₂X (X = F, Cl, Br) with [¹⁸F]fluoride represents a traditional way to access ¹⁸F-labeled trifluoromethyl motifs. For example, ¹⁸F-labeled aryl-CF₃ could be obtained by either ¹⁹f/¹⁸F isotope exchange, or halogen-¹⁸F exchange with aryl-ClF₂ or -BrF₂ as shown in the synthesis of ¹⁸F-celecoxib (Scheme 28).^[158] Since the presence of two α-fluorine severely inhibits displacement reactions with [¹⁸F]fluoride, harsh conditions including corrosive reagents and high temperature, are usually employed, thus limiting the compatibility with well-functionalized groups.

Scheme 28.

Traditional halogen-¹⁸F exchange reactions

In recent years, Ag(I) was found to be an accelerant for halogen-¹⁸F exchange under mild reaction conditions. In 2015, Gouverneur et al. found aryl-SCF₂Br, -OCF₂Br, -OCHFCl precursors could be converted to ¹⁸F-labeled aryl-SCF₃, -OCF₃ and -OCHF₂ groups, respectively, in the presence of AgOTf (Scheme 29A).^[159] Subsequently, they also found AgOTf could promote the formation of a broad array of ¹⁸F-labeled aryl-CF₃ and aryl-CF₂H from the corresponding aryl-CF₂Br and aryl-CHFCl precursors, respectively (Scheme 29A).^[160] Another Ag(I) application entailed the synthesis of ¹⁸F-labeled Umemoto reagent for trifluoromethylthiolation by Gouverneur et al. (Scheme 29B).^[161] The reagent was synthesized from an oxidative ring closure of ¹⁸F-labeled [1,1’-biphenyl]-4- yl(trifluoromethyl)-sulfane. ¹⁸F-Trifluoromethylthiolation was tolerated with various functional groups and exhibited high chemoselectivity for the radiolabeling of the cysteine residue of unmodified peptides. An α_vβ₃ integrin-targeted peptide (cRGDfC- [¹⁸F]SCF₃) was prepared in 19% RCY with 0.15 GBq/μmol molar activity.

Scheme 29.

Facilitated halogen-¹⁸F exchange for [¹⁸F]CF₃/[¹⁸F]CF₂H formation

Metal-free halogen-¹⁸F approaches via activating groups have also been developed in recent years. In 2016, a practical method for ¹⁸F-labeled aryl-CF₂H compounds was developed by the Ritter, Vasdev and Liang groups (Scheme 29C).^[162] The desired product was generated in a highly efficient ‘one-pot’ sequence, including C-H bromination to generate α-Br-α-F- acetophenone in situ, followed by facilitated ¹⁸F/Br-exchange at the α position of the carbonyl group and subsequent benzophenone cleavage. A number of well-functionalized ¹⁸F- difluoromethylarene analogs including fenofibrate, Claritin and fluoxetine was efficiently synthesized. In the same year, Liang et al. developed another metal-free oxidative C-H activation method for ¹⁸F-labeled aryl-CF₂H compounds (Scheme 29D).^[163] The procedure involved the conversion of benzyl halides into aryl- [¹⁸F]CFH₂, followed by oxidative C-H activation and fluorination. The method was well tolerated with a diverse range of electron- donating and -neutral functional groups with 10–45% RCCs, and achieved the highest molar activity of 22 GBq/μmol for aryl- [¹⁸F]CF₂H compounds to date.

3.3.2. ¹⁸F-Labeled aryl-CF₃ groups via transition metal-mediated cross coupling

The preparation of aryl-CF₂X (X = Cl or Br) as labeling precursors is challenging and involves multi-step synthesis in most cases, which limits the substrate scope of halogen-¹⁸F exchange method. In 2013, Passchier and Gouverneur et al. introduced an efficient method for aromatic ¹⁸F- trifluoromethylation of aryl iodides with Cu(I) catalyst (Scheme 30, A1).^[164] [¹⁸F]CuCF₃ was proposed to generate in situ from CuI,

Scheme 30.

Cu(I)-mediated ¹⁸F-labeled CF₃ formation via [¹⁸F]fluoride and difluorocarbene

ClCF₂CO₂Me (a difluorocarbene reagent) and [¹⁸F]fluoride in the presence of TMEDA. This procedure was operationally simple and tolerated with a variety of functional groups with high RCYs. Another Cu(I)-mediated ¹⁸F-trifluoromethylation using CHF₂I to generate [¹⁸F]CuCF₃ was reported by Riss et al. in 2014.^[165] Several representative ¹⁸F-labeled CF₃ molecules, including [¹⁸F]flutamide, [¹⁸F]trifluorothymine and ¹⁸F-labeled Boc-protected piperazine were synthesized by these methods (Scheme 30, A2).

Other than the ‘one-pot’ protocol, a stepwise procedure for [¹⁸F]CuCF₃ formation with isolated [¹⁸F]HCF₃ was also viable. In 2014, Vugts et al. employed cross coupling reactions between [¹⁸F]CuCF₃ and aryl iodides or boronic acids, to generate ¹⁸F- labeled CF₃ motifs (Scheme 30, B1).^[166] Et3N· 3HF was added to stabilize [¹⁸F]CuCF₃^[167] so that this method could offer an increased molar activity of ¹⁸F-labeled products to 25 GBq/μmol. The [¹⁸F]HCF₃ was also used in the reactions with ketones and aldehydes.^[168] Using a difluoromethyl sulfonium salt as difluorocarbene regent, Jubault and Labar et al. developed an alternative method to generate [¹⁸F]HCF₃ (Scheme 30, B2), which was used for the formation of [¹⁸F]CuCF₃ and subsequent ¹⁸F- trifluoromethylation in high RCYs (78–88%).^[169]

Other than Cu-mediated cross coupling reactions, Carroll et al. developed site-selective oxidative fluorination of benzylic difluoromethyl groups with Mn(salen)Cl.^[170] Based on the mechanism of ¹⁸F-transfer with Mn catalyst,^{[106] 18}F-labeled CF₃ groups could be obtained in 16–61% RCYs except for a few electron-deficient derivatives.

3.3.3. ¹⁸F-Labeled alkyl-CF₃ compounds

¹⁸F-Labeled trifluoroethyl tosylate can be obtained either by ¹⁹F/¹⁸F exchange^[171] or ¹⁸F-addition of 2,2-difluorovinyl tosylate (Scheme 31A-B).^[172, ^173] Using the protocol in Scheme 31B, ¹⁸F- labeled trifluoroethyl tosylate could further react with nucleophiles, including phenols, carboxylic acids and amines, in 77–93% RCYs. As PET imaging application, Scott et al. used this strategy to produce [¹⁸F]lansoprazole in 4–14% RCYs with 37 GBq/μmol molar activity.^[174]

Scheme 31.

Formation of ¹⁸F-labeled alkyl-CF₃ compounds

In 2017, Toste and O’Neil et al. reported a novel method for borane-catalyzed ¹⁸F-labeled alkyl-CF₃ compound formation from Au(III) complex (Scheme 31C).^[175] Treatment with [¹⁸F]KF and B(C₆F₅)₃, Au(III)-OAc complex was converted to alkyl-[¹⁸F]CF₃ compound via ligand exchange and reductive elimination. Three representative alkyl-CF₃ analogs were labeled in reasonable RCCs, and [¹⁸F]BAY 59–3074 was isolated with 6% RCY and 0.3 GBq/μmol molar activity.

3.3.4. ¹⁸F-Labeled alkyl- and aryl-SCF₃/SeCF₃ groups via difluorocarbene

Complementary to Ag(I)-accelerated exchange method of aryl-SCF₂X, Jubault and Labar et al. prepared ¹⁸F-labeled aryl- SCF₃ or -SeCF₃ from disulfides or diphenyl diselenides with [¹⁸F]fluoroform, respectively (Scheme 32A).^[176] Different sulfur- containing derivatives including 2-(phenylthio)isoindoline-1,3- dione and S-phenyl benzenesulfonothioate could also produce the desired product in 84–99% RCYs.

Scheme 32.

¹⁸F-Labeled SCF₃/SeCF₃ formation with [¹⁸F]fluoride and :CF₂

Despite impressive progress has been achieved in synthesis of ¹⁸F-labeled aromatic-SCF₃ compounds, ¹⁸F- trifluoromethylthiolation on aliphatic carbon was challenging until Liang and Xiao et al. reported an effective method in 2015.^{[177] 18}F- Labeled SCF₃ anion generated in situ from [¹⁸F]fluoride, S₈ and Ph₃P⁺CF₂CO₂⁻ (PDFA, a novel difluorocarbene reagent^[178]), was reported to enable ¹⁸F-trifluoromethylthiolation of alkyl electrophiles (Scheme 32, B1). The method was compatible with aliphatic substrates bearing electron-withdrawing or -donating groups in 22–83% RCCs. Subsequently, the authors found α- bromo carbonyls could also be converted to α-[¹⁸F]SCF₃ carbonyls (Scheme 32, B2).^[179] An unconventional reaction mechanism was discovered in the formation of alkyl-SCF₃ compounds by the identification of a key intermediate, thiocarbonyl fluoride.

3.4. Non-canonical ¹⁸F-labelings via bond formations with B, Si, Al, Ga and S

A diverse array of noncanonical ¹⁸F-labelings via bond formations with B, Si, Al, Ga and S have been established in the past decades.^{[86, 88]} In 2005, Perrin et al. reported the first example of ¹⁸F-labeling of biomolecules via ¹⁸F-B bond formation (Scheme 33A).^[180] A board range of ¹⁸F-labeled arylfluoroborates, generated from pinacol boronate esters, borimidines and trifluoroborates, were utilized.^[180–182] Recently, a new aliphatic trifluoroborates stabilized by adjacent ammonium groups (in a zwitterionic form) developed by Perrin et al. was demonstrted in the synthesis of a number of clinically relevant peptides.^[183] Other labeled molecules via B-¹⁸F bond formation have been showcased in the synthesis of [¹⁸F]BODIPY,^[184, ^185] NHC-[¹⁸F]BF₃ adduct^[186] and [¹⁸F]tetrafluoroborate through halogen-¹⁸F exchange.^[187] Recently Chen and Liu et al. reported several ¹⁸F- labeled boramino acids (replacement of COO⁻ in amino acids with BF₃⁻), synthesized by the ¹⁸F-B method, for imaging amino acid transporters.^[188]

Scheme 33.

Non-canonical ¹⁸F-labeling methods

In 2006, Jurkschat and Schirrmacher et al. reported the synthesis of stable [¹⁸F]fluorosilanes via ¹⁹f/¹⁸F exchange (Scheme 33, B1).^[189] Their silicon-based fluoride acceptor (SiFA) methodology took advantage of two bulky teri-butyl groups to shield Si-¹⁸F bond and showed excellent in vitro stability. To further reduce high lipophilicity of silicon building blocks, structural modifications including PEGylation and/or zwitterion scaffold were further developed.^[190] In parallel, Klar and Ametamey et al. reported the synthesis of [¹⁸F]fluorosilanes via H/¹⁸F or OH/¹⁸F exchange of dialkylsilane precursors (Scheme 33, B2).^[191] These ¹⁸F-Si bond formation methods were successfully applied in the ¹⁸F-labeling peptides, including Tyr³-octreotate and bombesin derivatives, with high efficiency.

In 2009, McBride et al. reported the first method utilizing ¹⁸F- Al bond formation to access radiolabeled peptides, where the Al-F complex was stabilized by a hexadentate chelating ligand, NOTA (Scheme 33, C1).^[192] The Al-¹⁸F chelation strategy has enriched the landscape for biomolecule labeling and showcased in the labeling of many thermostable peptides, including IMP467, dimeric RGDyK and folate receptor-targeting peptides.^[88] Recently, new chelators for ¹⁸F-Al complex formation were developed by Bormans et al. to tackle with heat-sensitive biologics. The new acyclic polydentate ligands possessed less rigid structure than macrocyclic NOTA, which substantially reduced activation energy for Al-F complexation, and exhibited rapid and efficient labeling with a diverse range of peptides and antibodies (including affibody & nanobody type) at 20–40°C (Scheme 33, C2&C3).^[193, ^194]

Recently Reid et al. developed a chelating strategy for the preparation of a series of ¹⁸F-labeled Ga compounds via halogen- ¹⁸F exchange.^[195–197] For example, [¹⁸F]GaF₃(BnMe₂-tacn) could be obtained by ¹⁹f/¹⁸F exchange in high RCYs (81 ± 1%; Scheme 33D). ¹⁸F-Labeled sulfur-containing molecules are also important building blocks and imaging agents,^[198] such as [¹⁸F]FS-PTAD prepared from chlorosulfonyl intermediate for bioconjugation with tyrosine residues,^[199] and [¹⁸F]SF₆, a ¹⁸F-labeled gas prepared via isotopic exchange for PET imaging assessment of lung ventilation (Scheme 33E).^[200]

3.5. Electrophilic ¹⁸F-fluorination with [¹⁸F]F₂ and [¹⁸F]F₂-derived reagents

3.5.1. Preparation of electrophilic [¹⁸F]F₂ reagents

The first and simplest electrophilic ¹⁸F-fluorination reagent is [¹⁸F]F₂, which can be produced via ²⁰Ne(d,α)¹⁸F or ¹⁸O(p,n)¹⁸F nuclear reaction using F₂ as carrier (Scheme 34). Molar activity of [¹⁸F]F₂ is usually in the range of 0.04–0.4 GBq/μmol. An improved preparation of [¹⁸F]F₂ was reported using [¹⁸F]CH₃F and a low amount of F₂, to (produce high molar activity up to 55 GBq/μmol).^[201] Attributed to high chemical reactivity of [¹⁸F]F₂, poor chemo- and regio-selectivity was often observed, resulting in low RCYs and technical challenges in purification. These limitations have stimulated the recent development of novel electrophilic ¹⁸F-fluorination reagents aimed for milder reactivity and higher selectivity. A range of electrophilic ¹⁸F-reagents were prepared from [¹⁸F]F₂ (Scheme 34), including previously reviewed^[5] [¹⁸F]XeF₂, [¹⁸F]CF₃OF, [¹⁸F]CH₃COOF, [¹⁸F]FClO₃, N- [¹⁸F]fluoropyridinium triflate, 1-[¹⁸F]fluoro-2-pyridone, and most recent [¹⁸F]NFSI^[202] and [¹⁸F]Selectfluor.^{[203, 204]}

Scheme 34.

Preparation of electrophilic ¹⁸F-fluorinating reagents

3.5.2. Electrophilic [¹⁸F]fluoroalkyl group formation

The original synthesis of [¹⁸F]FDG was conducted via electrophilic ¹⁸F-fluorination, albeit in low RCY and accompanied with undesired regioisomers (Scheme 35, A1).^[205] The analogous reaction was also applied in the electrophilic ¹⁸F-fluorination of electron-deficient fluorinated alkenes, such as [¹⁸F]EF5 (Scheme 35, A2).^[206] The recent development of [¹⁸F]F₂-derived reagents, such as [¹⁸F]NFSI, provided a new opportunity for enantio- and diastereo-selective ¹⁸F-fluorination. In 2015, Gouverneur et al. developed an organocatalyst-mediated enantioselective ¹⁸F- fluorination of aldehydes with [¹⁸F]NFSI (Scheme 35B).^[207] The ‘one-pot’ reaction was commenced with a chiral imidazolidinone and [¹⁸F]NFSI, followed by oxidation of CHO to COOH and deprotection, to provide ¹⁸F-labeled amino acids. For instance, (2S,4S)-4-[¹⁸F]fluoroglutamic acid was synthesized in 62% RCC with high enantioselectivity (>99% ee) and high diastereoselectivity (19:1 d.r). In 2017, Britton, Schaffer, Bénard and Martin et al. reported a selective photocatalytic ¹⁸F- fluorination of nonactivated C-H bonds with [¹⁸F]NFSI (Scheme 35C).^[208] The reaction was initiated by abstracting H from the aliphatic chain using photoactivated decatungstate catalyst, followed by [¹⁸F]fluorine atom transfer from [¹⁸F]NFSI. As proof of concept, branched aliphatic amino acids 4-[¹⁸F]fluoroleucine (4- [¹⁸F]FL) and 5-[¹⁸F]fluorohomoleucine (5-[¹⁸F]FHL) were synthesized in 23% and 28% RCYs, respectively.

Scheme 35.

Electrophilic ¹⁸F-fluorination for ¹⁸F-alkyl formation

3.5.3. Electrophilic [¹⁸F]fluoroarene formation

The most representative electrophilic aromatic ¹⁸F- fluorination entails the synthesis of 6-[¹⁸F]FDOPA. It was first synthesized from electrophilic aromatic substitution of 3,4- dihydroxy-phenyl-L-alanine with [¹⁸F]F₂ in low RCYs and low regioselectivity. Electrophilic ¹⁸F-fluorination of aryl organometallic reagents was regioselective compared with direct electrophilic ¹⁸F-fluorination. As a result, the synthesis was improved to 25% RCY by a regioselective radiofluorodestannylation (Scheme 36A).^[209] Another direction to improve regioselectivity of electrophilic ¹⁸F-fluorination involved the use of milder electrophilic ¹⁸F-fluorinating reagents, such as [¹⁸F]NFSI^[207]206] and more recently, [¹⁸F]Selectfluor in the Ag- mediated ¹⁸F-fluorination of arylstannanes or arylboronic esters precursors for [¹⁸F]FDOPA synthesis reported by Gouverneur et al. (Scheme 36B-C).^{[203, 204]}

Scheme 36.

Electrophilic ¹⁸F-fluorination for arenes

4. Labeling methods with nitrogen-13 and oxygen-15

Considering the extremely short half-lives of ¹⁵O (t_1/2 = 2.04 min) and ¹³N (t_1/2 = 9.97 min), it is challenging to perform multiple- step radiochemical synthesis of complex molecules compared to ¹⁸F. Automated inline production of ¹⁵O and ¹³N agents is often used to improve the synthesis efficiency and quality, so that repetitive PET studies can be conducted on the same subject within a short study period. Together with previous ¹³N and ¹⁵O reviews,^{[210, 211]} we highlight the recent development of major synthons and transformations.

4.1. ¹³N chemistry

Nitrogen-13 is routinely produced by nuclear reactions ¹⁶O(p,α)¹³N, ¹²C(p,n)¹³N or ¹³C(p,n)¹³N in the cyclotron (Scheme 37A).^[212] [¹³N]NH₃, widely used in clinical PET imaging for cardiovascular diseases^[213] and glutamate metabolism,^[214] was produced by proton irradiation of water.^[212] [¹³N]NH₃ could also serve as a building block for ¹³N transformations including enzymatic reaction, Hofmann rearrangement, amide or imine reduction, amination of organoboranes, substitution or amidation. These reactions were used to prepare ¹³N-labeled amino acids, primary amines, amides, ureas, carbamates and metal complexes (Scheme 37B).^{[212, 215–217]}

Scheme 37.

¹³N chemistry

[¹³N]NO₂⁻ is another commonly used synthon for ¹³N chemistry, which can be prepared by proton irradiation of water, oxidation of [¹³N]NH₃ using gallium or cobalt oxides, or reduction of [¹³N]NO₃⁻ through metals or eukaryotic nitrate reductase (Scheme 37A).^{[212, 218, 219] 13}N-Nitrosation of ureas, secondary amines and thiols could be realized via [¹³N]NO₂⁻.^{[218, 220]} For example, GSNO, a most widely studied S-nitrosothiol, was synthesized in 24% RCY.^[218] [¹³N]NO₂⁻ is also used to prepare ¹³N-labeled diazo^{[221, 222]} and azido^[223] compounds via diazonium intermediate. The ensuing ¹³N-labeled azido compounds can be further used in the cyclization reactions to form [¹³N]triazoles,^[224] [¹³N]tetrazoles,^[225] and a furaxan analog [¹³N]PRG150 (Scheme 37C).^[226] Other ¹³N-labeling agents, such as [¹³N]N₂ and [¹³N]N₂O, were reported as well. ^{[212, 227]}

4.2. ¹⁵O chemistry

The short half-life of ¹⁵O necessitates rapid and single-step- preferred radiosynthetic process. [¹⁵O]O₂ gas, produced from ¹⁴N(d,n)¹⁵O nuclear reaction, is the feedstock virtually for all ¹⁵O- labeled tracers. The synthetic routes and PET imaging applications are depicted in Scheme 38. The [¹⁵O]O₂ was converted to other ¹⁵O gases including [¹⁵O]CO₂, [¹⁵O]CO and [¹⁵O]N₂O under appropriate reductive or oxidative conditions at high temperature.^{[228, 229]} Other essential tracers, for example, [¹⁵O]H₂O₂, [¹⁵O]butanol and 6-[¹⁵O]-2-deoxy-D-glucose, were also efficiently prepared by the one-step reaction.^[230–232]

Scheme 38.

¹⁵O chemistry

The most important ¹⁵O-labeled PET tracer is [¹⁵O]H₂O, commonly used for the study of regional cerebral blood flow and metabolism.^[233] Several methods for the production of [¹⁵O]H₂O have been reported,^[5] including direct bombardment of water using ¹⁶O(p,pn)¹⁵O reaction, reaction of [¹⁵O]O₂ with H₂ over Pt or Pd at high temperature, and in vivo ¹⁵O exchange of [¹⁵O]CO₂ by carbonic anhydrase.

5. Summary and Outlook

Small molecule PET ligand discovery has long been hampered by the stringent constraints imparted by challenges in working with the short-lived radionuclides, ¹¹C, ¹⁸F, ¹³N and ¹⁵O. Over the last decade, we have observed a rapid growth in PET radiochemistry, partially driven by the growing importance of PET imaging in pharmaceutical research, yielding a plethora of exciting new methodologies that equipped researchers with not only greater synthetic options, but also a broader scope of functional groups. These advances provide greater flexibility when designing new PET ligands, with optimized pharmacological, physicochemical and ADME properties. Among several new ¹⁸F-fluorination methods for labeling non-activated arenes, the most advanced for human use at this time are the hypervalent iodine(III) methods (diaryl iodonium salts and iodonium ylides). Copper-mediated radiofluorination using boron/tin precursors is also promising for clinical translation. In ¹¹C chemistry, carbonylation via [¹¹C]CO₂ fixation has advanced to human use and has been useful for ¹¹C-labeled carbamates, unsymmetrical ureas, carboxylic acids, amides and oxazolidinones. More advanced methods and board substrate scope for ¹¹C-labeled amides and nitriles have been seen in the transition metal mediated cross coupling reactions with [¹¹C]CO.

It is important, however, to realize that many emerging methodologies were established primarily using simple substrates with minimal functionalizations. Broad functional group toleration and robustness of a given methodology need to be rigorously assessed to gain a realistic understanding on its suitability in PET labeling of fully elaborated drug-like molecules. Other promising but underdeveloped areas may also include electrophilic fluorination and multifluoromethylation in high specific activity, electrochemical or light-induced reactions, radiolabeling of unmodified biologics under physiological conditions. Although it may be unrealistic to think of ¹³N and ¹⁵O as substitutes for ¹¹C or ¹⁸F, these radionuclides are rarely considered by PET chemists and have potential for generating an arsenal of new radiotracers. Furthermore, with any new labeling methodology, amenability to simple purification, automation, quality control, and most importantly GMP practice needs to be considered upfront to ensure a clear pathway into the clinic. Finally, efforts toward expansion of functional groups that are amenable to radiolabeling with PET nuclides will increase the probability of successfully identifying PET ligands to guide the development of life-saving therapeutics.

Biography

Steven H. Liang obtained his B.S. at Tianjin University, followed by his Ph.D. in Chemistry with Professor Marco Ciufolini in the University of British Columbia. Then he started as a NSERC fellow with Professor EJ Corey at Harvard University. Dr. Liang is currently the Director of Radiochemistry and Biomarker Development Program, Nuclear Medicine and Molecular Imaging at Massachusetts General Hospital and Assistant Professor of Radiology at Harvard Medical School.