Nickeisha A. Stephenson

Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics

Fluorine-18 (t½=109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [(18)F]fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general (18)F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with [(18)F]fluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta-substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive (18)F-labelled building blocks, compounds and radiopharmaceuticals are synthesized.

Application of Palladium-Mediated 18F-Fluorination to PET Radiotracer Development: Overcoming Hurdles to Translation

New chemistry methods for the synthesis of radiolabeled small molecules have the potential to impact clinical positron emission tomography (PET) imaging, if they can be successfully translated. However, progression of modern reactions from the stage of synthetic chemistry development to the preparation of radiotracer doses ready for use in human PET imaging is challenging and rare. Here we describe the process of and the successful translation of a modern palladium-mediated fluorination reaction to non-human primate (NHP) baboon PET imaging–an important milestone on the path to human PET imaging. The method, which transforms [18F]fluoride into an electrophilic fluorination reagent, provides access to aryl–18F bonds that would be challenging to synthesize via conventional radiochemistry methods.

Iodonium Ylide Mediated Radiofluorination of 18F-FPEB and Validation for Human Use

Translation of new methodologies for labeling nonactivated aromatic molecules with 18F remains a challenge. Here, we report a one-step, regioselective, metal-free 18F-labeling method that uses a hypervalent iodonium(III) ylide precursor, to prepare the radiopharmaceutical 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-FPEB). Methods: Automated radiosynthesis of 18F-FPEB was achieved by reaction of the ylide precursor (4 mg) with 18F-Et4NF in dimethylformamide at 80°C for 5 min and formulated for injection within 1 h. Results: 18F-FPEB was synthesized in 20% ± 5% (n = 3) uncorrected radiochemical yields relative to 18F-fluoride, with specific activities of 666 ± 51.8 GBq (18 ± 1.4 Ci)/μmol at the end of synthesis and was validated for human use. Conclusion: Radiofluorination of iodonium (III) ylides proved to be an efficient radiosynthetic strategy for synthesis of 18F-labeled radiopharmaceuticals.

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque †

Alzheimers disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [(11) C]-PiB and [(18) F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted.

Synthesis and preliminary PET imaging of 11 C and 18 F isotopologues of the ROS1/ALK inhibitor lorlatinib

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood–brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.

Metal-free 18F-labeling of aryl-CF2H via nucleophilic radiofluorination and oxidative C–H activation

A metal-free and selective method to form [18F]aryl-CF2H through nucleophilic radiofluorination of benzyl (pseudo)halides and oxidative C-H activation of benzylic C-H bonds has been developed. The method is operationally simple and tolerates a variety of electron-neutral/deficient arenes and heteroarenes.

Recent applications of a single quadrupole mass spectrometer in 11C, 18F and radiometal chemistry

Mass spectrometry (MS) has longstanding applications in radiochemistry laboratories, stemming from carbon-dating. However, research on the development of radiotracers for molecular imaging with either positron emission tomography (PET) or single photon emission computed tomography has yet to take full advantage of MS. This inertia has been attributed to the relatively low concentrations of radiopharmaceutical formulations and lack of access to the required MS equipment due to the high costs for purchase and maintenance of specialized MS systems. To date, single quadrupole (SQ)-MS coupled to liquid chromatography (LC) systems is the main form of MS that has been used in radiochemistry laboratories. These LC/MS systems are primarily used for assessing the chemical purity of radiolabeling precursor or standard molecules but also have applications in the determination of metabolites. Herein, we highlight personal experiences using a compact SQ-MS in our PET radiochemistry laboratories, to monitor the small amounts of carrier observed in most radiotracer preparations, even at high molar activities. The use of a SQ-MS in the observation of the low mass associated with non-radioactive species which are formed along with the radiotracer from the trace amounts of carrier found is demonstrated. Herein, we describe a pre-concentration system to detect dilute radiopharmaceutical formulations and metabolite analyses by SQ-MS. Selected examples where SQ-MS was critical for optimization of radiochemical reactions and for unequivocal characterization of radiotracers are showcased. We also illustrate examples where SQ-MS can be applied in identification of radiometal complexes and development of a new purification methodology for Pd-catalyzed radiofluorination reactions, shedding light on the identity of metal complexes present in the labelling solution.